Pharmaceutical suspensions containing drug particles, devices for their administration, and methods of their use

ABSTRACT

The invention features a pharmaceutical suspension containing drug particles, a drug delivery device anchored in the mouth for continuously administering the pharmaceutical suspension, and methods of their use.

FIELD OF THE INVENTION

The invention features a pharmaceutical suspension containing drugparticles, a drug delivery device anchored in the mouth for continuouslyadministering the pharmaceutical suspension, and methods of their use.

BACKGROUND

This invention relates to devices and methods for continuous orsemi-continuous drug administration via the oral route. It is an aim ofthis invention to solve several problems related to drugs with shortphysiological half-lives of drugs (e.g., shorter than 8 hours, 6 hours,4 hours, 2 hours, 1 hour, 30 min, 20 min or 10 min) and/or narrowtherapeutic windows of drugs that are currently dosed multiple times perday: it is inconvenient to take a drug that must be dosed multiple timesper day or at night, the drug's pharmacokinetics and efficacy may besub-optimal, and side effects may increase in frequency and/or severity.Continuous or semi-continuous administration can be particularlybeneficial for drugs with a short half-life (e.g., in the plasma),and/or short persistence of the drug's physiological effect, and/or anarrow therapeutic window, such as levodopa (LD), muscle relaxants (e.g,baclofen for managing spasticity), anti-epileptics (e.g., oxcarbazepine,topiramate, lamotrigine, gabapentin, carbamazepine, valproic acid,levetiracetam, pregabalin), parasympathomimetics (e.g., pyridostigmine)and sleep medications (e.g., zaleplon). Continuous or semi-continuousinfusion in the mouth can provide for lesser fluctuation in theconcentration of a drug in an organ or fluid, for example in the bloodor plasma. Convenient, automatic administration of a drug can alsoincrease patient compliance with their drug regimen, particularly forpatients who must take medications at night and for patients withdementia.

Medical conditions managed by continuously orally administered drugsinclude Parkinson's disease, spasticity, muscular weakness, bacterialinfections, cancer, pain, organ transplantation, disordered sleep,epilepsy and seizures, anxiety, mood disorders, post-traumatic stressdisorder, arrhythmia, hypertension, heart failure, dementia, allergies,and diabetic nephropathy.

A challenge with most drug delivery devices in the prior art can be thatthey are not designed for placement and operation in the mouth. Devicesmust be designed to be small, comfortable, and non-irritating, and tonot interfere with speech, swallowing, drinking and/or eating. In themouth saliva, food or drink may penetrate into the drug reservoir and/orthe pump, thereby potentially unpredictably extracting and deliveringthe drug, reacting with the drug, or clogging the delivery device. Pumpsthat have been suggested for operation in the mouth, such as osmotictablets and mucoadhesive patches, often do not reliably provide constantrate drug delivery for extended periods of time under the conditions inthe mouth. Drinking of hot or cold beverages may cause undesirablechanges in drug delivery, e.g., delivery of a drug bolus. Likewise,sucking on the device may cause delivery of an unwanted bolus. Exposureto foods and liquids such as oils, alcohols, and acids may temporarilyor permanently increase or decrease the drug delivery rate from thedevice. Intra-oral drug delivery devices must also administer the druginto a suitable location in the mouth, e.g., to a location where it canbe immediately swallowed or to a location where the drug does notaccumulate in an unwanted manner. There is, therefore, a need forimproved drug delivery devices that can operate comfortably, safely, andreliably in the mouth over extended periods of time.

Intra-oral pumps have previously been proposed in inconvenient formats,e.g., wherein the device can be located within a replacement tooth.There is a need for improved intra-oral drug delivery devices that canconveniently be inserted and removed by the patient, without requiringthe insertion or removal of a replacement tooth, dental bridge, ordenture. A problem with these and other pumps that reside in the mouthand that can continuously deliver drug in the mouth, such as controlledrelease osmotic tablets and muco-adhesive drug delivery patches, can bethat once drug delivery has begun it cannot be temporarily stopped.Temporarily stopping the drug delivery can be desirable so that drug isnot wasted and, more importantly, so that dispensed drug does notaccumulate on the surface of the device while the device is removed fromthe mouth. Such an unquantified accumulation of drug on the surface ofthe device might lead to the undesired delivery of a bolus of an unknownquantity of drug to the patient when the device is placed back into themouth. Maintenance of accurate rate of drug delivery when the ambientatmospheric pressure changes, e.g., during air-travel or at elevatedlocations, can also be challenging.

The pumps of the invention can provide constant rate, continuousadministration of drugs in the mouth, and in some embodiments can betemporarily stopped when the devices are removed from the mouth.

Most drugs intended for oral administration have been formulated assolids (e.g., pills, tablets), solutions, or suspensions that areadministered once or several times per day. Such drugs are notformulated to meet the requirements of continuous or semi-continuous,constant-rate, intra-oral administration. For example, many suspensionsand solutions have been formulated in relatively large daily volumesthat don't fit in the mouth without interfering with its functions,particularly with speech, and/or in formulations that are physically orchemically unstable over the course of a day at body temperature; andpills and tablets have rarely been formulated in units and dosageamounts appropriate for dosing frequently throughout the day.

Large quantities of drug must be administered to treat some diseases.For example, 1,000 mg of levodopa is a typical daily dose administeredto patients with advanced Parkinson's disease. In order to continuouslyadminister such large quantities of drug into the mouth in a fluidvolume that will fit comfortably in the mouth (typically less than 5 mL)for many hours, it is sometimes necessary to employ concentrated, oftenviscous, fluid formulations of the drug. Use of viscous fluids canprovide the small volumes, high concentrations, uniform drug dispersion,storage stability, and operational stability desired for the drugs andmethods of the invention. Consequently, it is often necessary to employminiaturized pumps tailored to provide the pressures required to pumpthe viscous fluids. The drug devices and formulations of the inventionaddress these unmet needs.

As a specific example, Parkinson's disease (PD) is characterized by theinability of the dopaminergic neurons in the substantia nigra to producethe neurotransmitter dopamine. PD impairs motor skills, cognitiveprocesses, autonomic functions, and sleep. Motor symptoms includetremor, rigidity, slow movement (bradykinesia), and loss of the abilityto initiate movement (akinesia) (collectively, the “off” state).Non-motor symptoms of PD include dementia, dysphagia (difficultyswallowing), slurred speech, orthostatic hypotension, seborrheicdermatitis, urinary incontinence, constipation, mood alterations, sexualdysfunction, and sleep issues (e.g., daytime somnolence, insomnia).

After more than 40 years of clinical use levodopa (LD) therapy remainsthe most effective method for managing PD and provides the greatestimprovement in motor function. Consequently, LD administration is theprimary treatment for PD. LD is usually orally administered. The orallyadministered LD enters the blood and part of the LD in the blood crossesthe blood brain barrier. It is metabolized, in part, in the brain todopamine which temporarily diminishes the motor symptoms of PD. As theneurodegeneration underlying PD progresses, the patients requireincreasing doses of LD and the fluctuations of brain dopamine levelsincrease. When too much LD is transported to the brain, dyskinesia setsin (uncontrolled movements such as writhing, twitching and shaking);when too little is transported, the patient re-enters the off state.Furthermore, as PD progresses, the therapeutic window for oralformulations of LD narrows, and it becomes increasingly difficult tocontrol PD motor symptoms without inducing motor complications. Inaddition, most PD patients develop response fluctuations to intermittentoral LD therapy, such as end of dose wearing off, sudden on/offs,delayed time to on, and response failures.

The devices, formulations and methods of the invention provide improvedtherapies for patients with PD.

SUMMARY OF THE INVENTION

The present invention features a pharmaceutical suspension containingdrug particles, a drug delivery device for continuously administeringthe pharmaceutical suspension to the oral cavity, and methods of usingthe same.

In a first aspect, the invention features a pharmaceutical compositionincluding a suspension, the suspension including (i) from about 35% toabout 75% (w/w) (e.g., from about 35% to about 70%, from about 35% toabout 65%, from about 35% to about 60%, from about 35% to about 55%,from about 35% to about 50%, from about 35% to about 45%, from about 35%to about 40%, from about 40% to about 45%, from about 40% to about 45%,from about 40% to about 50%, from about 40% to about 55%, from about 40%to about 60%, from about 40% to about 65%, from about 40% to about 65%,from about 40% to about 70%, from about 40% to about 75%, from about 45%to about 75%, from about 50% to about 75%, from about 55% to about 75%,from about 60% to about 75%, from about 65% to about 75%, from about 70%to about 75%, or from about 50% to about 65%) drug particles includinglevodopa and/or carbidopa, or salts thereof, (ii) from about 19% toabout 30% (w/w) (e.g., from about 19% to about 28%, from about 19% toabout 26%, from about 19% to about 24%, from about 19% to about 22%,from about 19% to about 21%, from about 21% to about 24%, from about 21%to about 30%, from about 24% to about 30%, from about 26% to about 30%,or from about 28% to about 30%) of one or more water-immisciblecompounds, (iii) from about 2% to about 16% (w/w) (e.g., from about 2%to about 15%, from about 2% to about 13%, from about 2% to about 12%,from about 2% to about 10%, from about 2% to about 8%, from about 2% toabout 6%, from about 2% to about 4%, from about 4% to about 13%, fromabout 6% to about 13%, from about 8% to about 13%, from about 6% toabout 10%, from about 10% to about 13%, or from about 13% to about 16%)water, and (iv) from about 1% to about 8% (w/w) (e.g., from about 1% toabout 7%, from about 1% to about 5%, from about 1% to about 3%, fromabout 3% to about 8%, or from about 5% to about 8%) surfactant, whereinthe pharmaceutical composition is physically stable and suitable forcontinuous or frequent intermittent intra-oral delivery. In someembodiments, the pharmaceutical composition includes a drugparticle-containing emulsion.

In a second aspect, the invention features a pharmaceutical compositionincluding a suspension including (i) from about 35% to about 75% (w/w)(e.g., as described herein) drug particles, (ii) from about 19% to about30% (w/w) (e.g., as described herein) of one or more water-immisciblecompounds, (iii) from about 2% to about 16% (w/w) (e.g., as describedherein) water, and (iv) from about 1% to about 8% (w/w) surfactant,wherein the pharmaceutical composition is physically stable and suitablefor continuous or frequent intermittent intra-oral delivery. In someembodiments, the pharmaceutical composition includes a drugparticle-containing emulsion. In other embodiments, the pharmaceuticalcomposition is macroscopically substantially homogeneous.

In a third aspect, the invention features a pharmaceutical compositionincluding a suspension including (i) an excess of one or morewater-immiscible compounds over water, and (ii) from about 35% to about75% (w/w) (e.g., as described herein) drug particles, wherein thepharmaceutical composition is physically stable (e.g., for 6 months, 8months, 10 months, 12 months, or more) at about 5° C. and/or about 25°C. In some embodiments, the pharmaceutical composition includes anemulsion (e.g., a drug particle-containing emulsion). In otherembodiments, the pharmaceutical composition is macroscopicallysubstantially homogeneous. In some embodiments, the pharmaceuticalcomposition is suitable for continuous or frequent intermittentintra-oral delivery.

In any of the preceding aspects, the suspension may be an extrudable,non-pourable emulsion. In some embodiments, the suspension is physicallystable for about 12 months at about 5° C. In other embodiments, thesuspension is physically stable for about 12 months at about 25° C. Incertain embodiments, after 12 months (e.g., after 13 months, after 14months, after 15 months, or more) the suspension is physically stablefor about 48 hours at about 37° C.

In any of the preceding aspects, the pharmaceutical composition mayinclude a continuous hydrophilic phase. The continuous hydrophilic phasecan provide for rapid dispersion of solid drug particle containingsuspensions in saliva and the well dispersed solid drug particles candissolve rapidly in saliva.

In any of the preceding aspects, the concentration of drug in apharmaceutical composition may be at least 1.75 M (e.g, more than 1.80M, 1.85 M, 1.90 M, 1.95 M, 2.0 M, 2.5 M, 3.0 M, or even 3.5 M). In someembodiments, the pharmaceutical composition includes from about 50% toabout 70% (w/w) (e.g., from about 50% to about 65%, from about 50% toabout 60%, from about 50% to about 55%, from about 55% to about 70%,from about 60% to about 70%, or from about 65% to about 70%) solid drugparticles, wherein the concentration of drug in the pharmaceuticalcomposition is at least 3.0 M (e.g., 3.1 M, 3.2 M, 3.5 M, or more).

In some embodiments, the suspension of any of the preceding aspectsincludes one or more water-immiscible compounds that melts or softensbelow 45° C. (e.g., at 40° C., 37° C., 35° C., or less). In someembodiments, the weight ratio of the one or more water-immisciblecompounds to water is greater than 1.0 (e.g., greater than 1.5, greaterthan 2.0, greater than 3.0, or greater than 5.0).

In some embodiments, the one or more water-immiscible compounds of anyof the preceding aspects includes an oil. In some embodiments, thesuspension includes a continuous hydrophilic phase including greaterthan 50% (w/w) (e.g., 55%, 60%, 65%, 70%, or 75%) drug particles. Incertain embodiments, the suspension includes an oil in water emulsion.In some embodiments, the suspension is free of polymers of a molecularmass greater than 1,000 Daltons (e.g., greater than about 1,100 Daltons,greater than about 1,200 Daltons, greater than about 1,500 Daltons,greater than about 1,700 Daltons, or greater than about 2,000 Daltons).In some embodiments, the suspension has a dynamic viscosity of at least100 cP (e.g., greater than 500 cP, 1,000 cP, 5,000 cP, 10,000 cP, 50,000cP, or 100,000 cP) at 37° C.

In any of the preceding aspects, the suspension may include greater than50% (w/w) (e.g., greater than 55%, greater than 60%, greater than 65%,or greater than 70%) drug particles. In some embodiments, the D₅₀ of thedrug particles can be less than or equal to about 500 μm, about 250 μm,about 200 μm, about 150 μm, about 125 μm, or about 100 μm. In someembodiments, the D₅₀ of the drug particles can be greater than or equalto about 1 μm, about 3 μm, about 5 μm, about 10 μm, or about 25 μm, orthe D₅₀ of the drug particles can be less than or equal to 50 μm such asless than or equal to 25 μm. In typical embodiments, the D₅₀ of the drugparticles can be 25±24 μm; 1-10 μm; 11-20 μm; 21-30 μm; 31-40 μm; or41-50 μm. In other embodiments, the D₅₀ of the drug particles can be75±25 μm; 51-75 μm; or 76-100 μm. In certain embodiments, the D₅₀ of thedrug particles can be 125±25 μm. In further embodiments, the D₅₀ of thedrug particles can be 175±25 μm.

In any of the preceding aspects, the suspension may include less than orequal to about 16% (w/w), about 13% (w/w), about 12% (w/w), about 11%(w/w), or about 9% (w/w) water. In some embodiments, the suspension caninclude greater than or equal to about 1% (w/w), about 2% (w/w), orabout 3% (w/w) water. In certain embodiments, the suspension can include4±2% (w/w) water. In particular embodiments, the suspension can include8±2% (w/w) water. In other embodiments, the suspension can include 13±3%(w/w) water.

In any of the preceding aspects, the one or more water-immisciblecompounds may include an oil selected from a saturated fatty acidtriglyceride, an unsaturated fatty acid triglyceride, a mixed saturatedand unsaturated fatty acid triglyceride, a medium-chain fatty acidtriglyceride, canola oil, coconut oil, palm oil, olive oil, soybean oil,sesame oil, corn oil, or mineral oil. In some embodiments, the oilcomprises a saturated fatty acid triglyceride or a mixture of saturatedfatty acid triglycerides. In other embodiments, the oil can be amedium-chain fatty acid triglyceride or a mixture of medium-chain fattyacid triglycerides. For example, the oil can be a Miglyol® or chemicalequivalent. In certain embodiments, the oil can be a canola oil. Inparticular embodiments, the oil can be a coconut oil. In someembodiments, the oil can be a triglyceride or one or more C₆-C₂₄ fattyacids, such as a triglyceride of one or more C₈-C₁₆ fatty acids. Forexample, the oil can be a triglyceride of C₈-C₁₂ fatty acids, C₁₄-C₁₈fatty acids, or C₂₀-C₂₄ fatty acids, or a mixture thereof. In someembodiments, at least 50% (w/w) of the one or more water-immisciblecompounds can be a triglyceride of one or more C₈-C₁₂ fatty acids. Incertain embodiments, the suspension can include less than or equal toabout 30% (w/w) (e.g., about 29% (w/w), about 27% (w/w), or about 25%(w/w)) of the oil. In particular embodiments, the suspension can includegreater than or equal to about 19% (w/w) (e.g., about 21% (w/w), orabout 23% (w/w)) of the oil. In certain embodiments, the suspension caninclude 20±2% (w/w) of the oil. In typical embodiments, the suspensioncan include 24±2% (w/w) of the oil. In some embodiments, the suspensioncan include 28±2% (w/w) of the oil.

In any of the preceding aspects, the pharmaceutical composition mayinclude a surfactant. A surfactant of a pharmaceutical composition maybe a non-ionic surfactant. In some embodiments, the non-ionic surfactantcan include a polyglycolized glyceride, a poloxamer, an alkylsaccharide, an ester saccharide, or a polysorbate surfactant. In certainembodiments, the non-ionic surfactant can include a poloxamer. In otherembodiments, the non-ionic surfactant can include a polyglycolizedglyceride such as a polyethoxylated castor oil. In particularembodiments, the non-ionic surfactant can include a polysorbatesurfactant that can be Polysorbate 60. In some embodiments, thesuspension can include less than or equal to about 8% (w/w) (e.g., about7% (w/w), about 6% (w/w), or about 5% (w/w)) of the surfactant. In someembodiments, the suspension can include greater than or equal to about2% (w/w) (e.g., about 3% (w/w) or about 4% (w/w)) of the surfactant. Incertain embodiments, the suspension can include about 5±2% (w/w) of thesurfactant.

In some embodiments, a pharmaceutical composition of any of thepreceding aspects can further include an antioxidant such as Vitamin E,TPGS, ascorbylpalmitate, a tocopherol, thioglycerol, thioglycolic acid,cysteine, N-acetyl cysteine, vitamin A, propyl gallate, octyl gallate,butylhydroxyanisole, or butylhydroxytoluene. In some embodiments, theantioxidant can be oil soluble. In other embodiments, the apparent pH ofthe suspension of any of the preceding aspects can be less than or equalto about 7.0, about 5.0, or about 4.0, the apparent pH being the pHmeasured by inserting an aqueous solution calibrated glass walled pHelectrode into the formulation at 23±3° C. In certain embodiments, theapparent pH can be greater than or equal to about 2.5, such as greaterthan or equal to 3.0 or 3.5. In some embodiments, the shelf life of thepharmaceutical composition can be 1 year or longer at 5±3° C. Inparticular embodiments, the shelf life of the pharmaceutical compositioncan be 1 year or longer at 25±3° C. For example, the apparent pH of thepharmaceutical composition can be less than pH 5 and can remain lessthan pH 5 after 3 months storage at about 25° C., can remain less thanpH 4 after 3 months storage at 25° C., or the apparent pH can equal orbe less than pH 3 after 3 months storage at about 25° C. Thepharmaceutical compositions can optionally include a bacteriostatic or afungistatic agent, such as benzoic acid or a benzoate salt. Inparticular embodiments, the combined concentrations of benzoic acid andbenzoate salt in the pharmaceutical composition can be between 0.1percent by weight and 1 percent by weight. The pharmaceuticalcompositions can optionally include a transition metal ion complexingagent or a salt thereof, such as EDTA. In particular embodiments, thecombined concentrations of EDTA and its salt or salts can be between0.05 weight % and 0.25 weight %. The pharmaceutical compositions canoptionally include a sulfur containing compound such as cysteine andN-acetylcysteine capable of reacting at 25±3° C. with dopaquinone orwith quinone formed by oxidation of carbidopa.

In any of the preceding aspects, the suspension of the drug particles ofa pharmaceutical composition may include levodopa or a levodopa prodrug,or carbidopa or a carbidopa prodrug, benserazide, or any mixturethereof. In particular embodiments, the suspension of the drug particlescan include levodopa and/or carbidopa. In some embodiments that includecarbidopa, the pharmaceutical composition can include less than about 2μg (e.g., less than 1.5 μg, 1.2 μg, 1.0 μg, 0.8 μg, or even less) ofhydrazine per mg of the one or more drugs after 1 week storage underambient air at about 60° C. In certain embodiments, the suspension ofthe drug particles can include carbidopa and the pharmaceuticalcomposition can further include less than about 8 μg (e.g., 7 μg, 6 μg,5 μg, 4 μg, 3 μg, 2 μg, or 1 μg) of hydrazine per mg of carbidopa after6 or 12 months storage at 5±3° C. or at 25±3° C.

In other embodiments, the drug particles can include one or moreallergens, allergen extracts, or allergen derivatives. For example, theone or more allergens can be pollen, a part of a mite, or a component ofthe feline or canine skin, or an extract or a conversion productthereof.

In any of the preceding aspects, the suspension may not cream orsediment when centrifuged for 1 hour at an acceleration of about 5,000 Gor greater (e.g., about 7,000 G, about 9,000 G, about 10,000 G, or about16,000 G) at 25±3° C. In some embodiments, the pharmaceuticalcomposition may not cream or sediment when stored for 12 months at 5±3°C. or 25±3° C. In some embodiments, after the centrifugation or storage,the concentrations of drug in the layer containing the top 20 volume %and the layer containing the bottom 20 volume % of the composition candiffer by less than 10%. In particular embodiments, after thecentrifugation or storage the concentrations of drug in the layercontaining the top 20 volume % and the layer containing the bottom 20volume % of the composition can differ by less than 6% (e.g., 5%, 4%,3%, 2%, 1%, or less). In any of these embodiments, after thecentrifugation or storage a pharmaceutical composition may exhibit novisible creaming or sedimentation.

In any of the preceding aspects, the pharmaceutical composition may havesubstantially no taste.

The invention features a pharmaceutical composition including asuspension including (i) from about 20% to about 80% (w/w) solidexcipients; (ii) from about 5% to 60% (w/w) drug particles, (iii) from19% to 30% (w/w) of one or more water-immiscible compounds, (iv) from 2%to 25% (w/w) water, and (v) from 1% to 10% (w/w) surfactant, wherein thepharmaceutical composition can be physically stable and suitable forcontinuous or frequent intermittent intra-oral delivery. Thepharmaceutical composition can include a paste or an emulsion. Inparticular embodiments, the suspension can be physically stable for 12months at 5° C., or can be physically stable for 12 months at 25° C., orafter the 12 months the suspension can be physically stable for 48 hoursat 37° C. The concentration of solid and/or dissolved drug in thepharmaceutical composition can be between about 50 mg/mL and about 1,000mg/mL (e.g., 50-500, 70±20, 150±60, or 350±150 mg/mL, 500±200 mg/mL,700±200 mg/mL, 800±200 mg/mL). In particular embodiments thepharmaceutical composition can include a solid excipient. The density ofthe solid excipient can be at about 25° C. between about 1.2 g/mL and3.5 g/mL such as between 1.2 g/mL and 1.8 g/mL. The concentration ofsolid excipient in the pharmaceutical composition can be between 200mg/mL and 1,500 mg/mL, such as between 200 and 800 mg/mL, or between 400and 800 mg/mL. In some embodiments, the excipient particles may notsubstantially swell in water and/or in the oil of the suspension. Insome embodiments, the D₅₀ of the excipient particles can be greater thanor equal to about 1 μm, about 3 μm, about 5 μm, about 10 μm, or about 25μm, or the D₅₀ of the excipient particles can be less than or equal to50 μm such as less than or equal to 25 μm. In typical embodiments, theD₅₀ of the excipient particles can be 25±24 μm; 1-10 μm; 11-20 μm; 21-30μm; 31-40 μm; or 41-50 μm. In other embodiments, the D₅₀ of theexcipient particles can be 75±25 μm; 51-75 μm; or 76-100 μm. In certainembodiments, the D₅₀ of the excipient particles can be 125±25 μm. Infurther embodiments, the D₅₀ of the excipient particles can be 175±25μm. In some embodiments, the solid excipient can include cellulose orcellulose derivatives that do not substantially swell in water or inoils, amino acids (such as tyrosine, phenyl alanine or cysteine),titanium dioxide, calcium silicate, or calcium phosphate.

In some embodiments, the drug in the pharmaceutical composition caninclude Baclofen, Tizanidine, Midodrine, Metoclopramide, Captopril,Treprostinil, Bitolterol, Oxybutinin, Darifenacin, pyridostigmine or apharmaceutically acceptable salt thereof. In a typical embodiment, thepharmaceutical composition can have a viscosity greater than 10,000 cPat 37° C. In one particular embodiment of any of the pharmaceuticalcompositions described herein, the drug is baclofen or a salt thereof,or the pharmaceutical composition includes baclofen or a salt thereof.In another embodiment of any of the pharmaceutical compositionsdescribed herein, the drug is pyridostigmine or a salt thereof, or thepharmaceutical composition includes pyridostigmine or a salt thereof.

The invention also features a pharmaceutical composition suitable forcontinuous infusion in the mouth including: a solution, an oil-in-wateremulsion, a water-in-oil emulsion, or a solid particle including asuspension of between 20 mg/mL and 150 mg/mL (e.g., 40±20, 75±25, or125±75 mg/mL) of a drug selected from Baclofen, Tizanidine, Midodrine,Metoclopramide, Captopril, Treprostinil, Bitolterol, Oxybutinin,Darifenacin. The pharmaceutical composition can further include athickener. In certain embodiments, the viscosity of the pharmaceuticalcomposition can be greater than 100 cP, 1,000 cP, or 10,000 cP at about37° C. In particular embodiments, the pharmaceutical composition canfurther include a surfactant.

The invention further features an extrudable pharmaceutical compositionsuitable for continuous infusion in the mouth having a pH of from 3 to10 (e.g., 5±2, 7±2, or 8±2) including a magnesium compound, a zinccompound, or an iron compound at a concentration between 60 mg/mL to1,600 mg/mL (e.g, 100±40, 600±200, or 1,300±300 mg/mL). Thepharmaceutical composition can further include a gelling agent or athickener. In particular embodiments, the viscosity of thepharmaceutical composition is greater than 1,000 cP, 10,000 cP, or100,000 cP at about 37° C.

In still other embodiments, the pharmaceutical composition can include amagnesium compound and the Mg²⁺ concentration in the pharmaceuticalcomposition can be greater than 200 mg/mL (e.g., 300±100, 500±150, or750±200 mg/mL).

The invention further features a pharmaceutical composition suitable forcontinuous infusion in the mouth including a solution, suspension or gelincluding between 0.1 mg/mL and 20 mg/mL of a drug selected fromTizanidine, Iloprost, Beraprost, Ciclesonide, Flunisolide, Budesonide,Beclomethasone, Mometasone, Vilanterol, Levosalbutamol sulfate,Salbutamol, Salmeterol, Glycopyrronium bromide, Ipatropium bromide,Aclidinium bromide, Hexoprenaline sulfate, Pirbuterol, Fenoterol,Terbutaline, Metaproterenol, Tolterodine tartarate. The pharmaceuticalcomposition can further include a gelling agent or a thickener. Inparticular embodiments, the viscosity of the pharmaceutical compositioncan be greater than 100 cP, 1,000 cP, or 10,000 cP at about 37° C. Inparticular embodiments, the pharmaceutical composition can furtherinclude a surfactant.

The invention features a drug delivery device configured to be removablyinserted in a patient's mouth and for continuous or semi-continuousintraoral administration of a drug, the device including apropellant-driven pump including a rigid housing, the rigid housingincluding a wall of a first chamber containing a drug-including fluidand a wall of a second chamber containing a propellant. The device caninclude a flexible and/or deformable propellant-impermeable diaphragmseparating the first chamber from the second chamber. The diaphragm caninclude a wall of the first chamber and a wall of the second chamber. Inparticular embodiments, the density of the propellant-impermeablediaphragm can be greater than 2.0 g per cm³ at 25° C. The diaphragm canbe metallic (e.g., tin or silver or aluminum or copper or an alloy oftin or of silver or of aluminum or of copper). Optionally, the metallicdiaphragm can comprise silver or an alloy of silver, or tin or an alloyof tin. The diaphragm can be shaped to substantially conform to theinterior housing wall of the first chamber and/or the interior housingwall of the second chamber. The diaphragm can be between 10 μm and 250μm thick, e.g., between 20 μm and 125 μm thick, such as between 25 μmand 75 μm thick. In particular embodiments, the thickness of thediaphragm can vary across the interior of the housing by less than ±25%,or by less than ±10%. In other embodiments, the diaphragm includes a rimthat is thicker than the center of the diaphragm (e.g., the thickness ofthe rim can be at least 1.5 times greater than the thickness of thecenter of the diaphragm, the thickness of the rim can be between 1.5times and 2 times the thickness of the center of the diaphragm, thethickness of the rim can be between 2 times and 3 times the thickness ofthe center of the diaphragm, or the thickness of the rim can be 3 timesor more the thickness of the center of the diaphragm). The diaphragm canbe folded, pleated, or scored. The device can be hermetically sealedexcept for one or more orifices for drug filling or drug delivery.Optionally, the one or more orifices for drug filling or drug deliverycan be hermetically or non-hermetically sealed. Optionally, the one ormore orifices for drug filling or delivery are hermetically sealed. Inparticular embodiments, the propellant chamber can be hermeticallysealed and can include a hermetically sealed orifice for filling withpropellant. In certain embodiments, the drug chamber can include two,three, or more hermetically sealable or sealed orifices for filling withdrug or for drug delivery. In still other embodiments, the rigid housingand the diaphragm can be joined by a hermetically sealing weld. Forexample, the hermetically sealing weld can prevent the influx of air andwater vapor or the outflux of water vapor, drug or propellant, orprevent the influx of air or oxygen, or prevent the influx or theoutflux of helium. In particular embodiments, the rigid housing of thedevice can include a metal, a ceramic, or a composite of a polymerreinforced by fibers (e.g., carbon fibers, glass fibers, or metalfibers). The rigid housing can include a material having at 25±3° C. ayield strength greater than 100 MPa, and/or having at 25±3° C. a tensileyield strength greater than 100 MPa, and/or having at 25±3° C. a modulusof elasticity greater than 30 GPa, and/or having at 25±3° C. a Brinellhardness greater than 200 MPa, and/or having a density greater than 2.5g/cm³ at 25±3° C., e.g., greater than 3.5 g/cm³ such as greater than 4.5g/cm³, or having a density equal to or greater than 5.5 g/cm³. The rigidhousing can include a metal selected from the group titanium or iron oraluminum or molybdenum or tungsten or an alloy of titanium or iron oraluminum or molybdenum or tungsten. In particular embodiments, the rigidhousing can include titanium or an alloy of titanium and a metallicdiaphragm (that can separate chambers within the housing) can be weldedto the rigid housing including titanium or an alloy of titanium. Incertain embodiments, the diaphragm can include silver or an alloy ofsilver or it can optionally include tin or an alloy of tin. In someembodiments, the diaphragm can include tin or an alloy of tin, or silveror an alloy of silver. In one embodiment, neither the metal of the rigidhousing nor the metal of the metallic diaphragm can corrode visiblyafter 3 months when the housing metal and the diaphragm metal areelectrically contacted and are immersed in an air exposed 0.1 M citratebuffer solution of pH 4.0 at 23±3° C.; or neither the metal of the rigidhousing nor the metal of the metallic diaphragm can corrode visiblyafter 3 months when the housing metal and the diaphragm metal areelectrically contacted and are immersed in a substantially de-oxygenated0.1 M citrate buffer solution of pH 4.0 at 23±3° C. The density of thecorrosion current flowing between two electrically shorted electrodes ofabout equal area, one of the metal of the rigid housing and the other ofthe metal of the diaphragm, can be less than 2 μA cm⁻², less than 0.5 μAcm⁻², or less than 0.1 μA cm⁻² after about 24 hour immersion of theelectrodes in a substantially de-oxygenated 0.1 M citrate buffersolution of pH 4.0 at 23±3° C.

In one particular embodiment, the shapes of the interior housing wall ofthe first chamber and the interior housing wall of the second chambercan be substantially mirror images of each other excepting for groovesor ports for flow of drug-including fluid to the drug exit orifice. Thefirst chamber can include one or more interior channels, grooves, ortubes for flow of drug-including fluid to the drug exit orifice. In oneembodiment, at least one channel, groove, or tube is not blocked by thediaphragm after more than 60 weight %, more than 75 weight %, more than85 weight %, or more than 95 weight % of the drug is depleted. Inanother embodiment, at least one channel, groove, or tube is not blockedby the diaphragm when the diaphragm has been fully extended into thedrug chamber and drug flow has substantially stopped. Optionally, ahousing wall can include the at least one channel, groove, or tube.Optionally, an insert can include the at least one channel, groove, ortube. In certain embodiments, the at least one channel, groove, or tubecan include one or more flow restrictors that substantially control therate of drug delivery. In certain embodiments, the diaphragm can beshaped and sized so that it contacts 0%-10%, 11%-20%, 21%-30%, 31%-40%,or 41%-50% of the interior surface area of the drug chamber (excludingthe surface area of the diaphragm itself) after delivery of 85%, 90%, or95% of the starting pharmaceutical composition in the drug chamber. Incertain embodiments, the diaphragm can be shaped and sized so that itdoes not substantially block the flow of the pharmaceutical compositionfrom the exit orifice after 85%, 90%, or 95% of the startingpharmaceutical composition in the drug chamber has been delivered.

In a related aspect, the invention features a method of forming thediaphragm for a delivery device of the invention, the method includingstamping, hot-stamping, electroplating, electroless plating, orhydroforming. The method can include welding the rigid housing and thediaphragm to form a hermetic seal by, e.g., resistance welding, laserwelding or electron beam welding. In particular embodiments, the methodcan also include preheating the housing and the diaphragm. The methodcan further include annealing at a temperature between 400° C. and 700°C. for 15 minutes or more.

In a related aspect, the invention features a drug delivery deviceconfigured to be removably inserted in a patient's mouth and forcontinuous or semi-continuous intraoral administration of a drug, thedevice including: a first chamber containing a drug-including fluid; asecond chamber containing a propellant; and a flexible and/or deformablediaphragm separating the first chamber from the second chamber, wherein75%-85%, 86%-95%, or >95% of the drug-including fluid can be dispensedwhile the delivery rate can vary by less than ±20%, ±15%, ±10%, or ±5%,over a period of at least 4, 8, 16, or 24 hours. The pump can include aliquid propellant, the liquid propellant having a boiling point of lessthan 37° C. at sea level atmospheric pressure. In particularembodiments, the liquid propellant can be a hydrocarbon, a halocarbon, ahydrofluoralkane, an ester, or an ether (e.g., the liquid propellant canbe isopentane, trifluorochloromethane, dichlorofluoromethane,1-fluorobutane, 2-fluorobutane, 1,2-difluoroethane, methyl ethyl ether,2-butene, butane, 1-fluoropropane, 1-butene, 2-fluoropropane,1,1-difluoroethane, cyclopropene, propane, propene, or diethyl ether).In certain embodiments, the liquid propellant is1,1,1,2-tetrafluoroethane, 1,1,1,2,3,3,3-heptafluoropropane,1,1,1,3,3,3-hexafluoropropane, octafluorocyclobutane or isopentane. Thepropellant can have a vapor pressure of greater than 1.5 bar and lessthan 20 bar at 37° C., such as a vapor pressure of greater than 2.0 barand less than 15 bar at 37° C., or a vapor pressure of greater than 3.0bar and less than 10 bar at 37° C. In some embodiments, (i) thepropellant can have a vapor pressure of greater than 2.1 bar at 37° C.,and (ii) the average rate of drug delivery can increase or decrease byless than ±20% across the atmospheric pressure range between 0.782 barand 1.013 bar. In other embodiments, (i) the propellant can have a vaporpressure of greater than 3.2 bar at 37° C., and (ii) the average rate ofdrug delivery can increase or decrease by less than ±10% across theatmospheric pressure range between 0.782 bar and 1.013 bar. In certainembodiments, (i) the propellant can have a vapor pressure of greaterthan 4.7 bar at 37° C., and (ii) the average rate of drug delivery canincrease or decreases by less than ±6% across the atmospheric pressurerange between 0.782 bar and 1.013 bar. The drug delivery device caninclude a reservoir containing any pharmaceutical composition describedherein.

In another aspect, the invention features a drug delivery deviceconfigured to be removably inserted in a patient's mouth and forcontinuous or semi-continuous intraoral administration of a drug, thedevice including: (i) a fastener to removably secure the drug deliverydevice to a surface of the patient's mouth; (ii) an electrical ormechanical pump; and (iii) an oral liquid impermeable drug reservoircontaining any of the pharmaceutical compositions of the invention, thevolume of the drug reservoir being from 0.1 mL to 5 mL (e.g., from 0.1mL to 4 mL, from 0.1 mL to 3 mL, from 0.1 mL to 2 mL, from 0.1 mL to 1mL, from 0.1 mL to 0.5 mL, from 0.1 mL to 0.25 mL, from 0.2 mL to 5 mL,from 0.3 mL to 5 mL, from 0.5 mL to 5 mL, from 1 mL to 5 mL, from 2 mLto 5 mL, from 4 mL to 5 mL, from 0.5 mL to 1 mL, from 0.5 mL to 2 mL,from 1 mL to 2 mL, from 2 mL to 3 mL).

In a further aspect, the invention features a drug delivery deviceconfigured to be removably inserted in a patient's mouth and forcontinuous or semi-continuous intraoral administration of a drug, thedevice including: (i) a fastener to removably secure the drug deliverydevice to a surface of the patient's mouth; (ii) an electrical ormechanical pump; (iii) an oral liquid impermeable drug reservoircontaining any of the pharmaceutical compositions of the invention, thevolume of the drug reservoir being from 0.1 mL to 5 mL (e.g., asdescribed herein); and (iv) an automatic stop/start.

In some embodiments, the drug delivery device can be configured to beautomatically stopped upon one or more of the following: (a) the drugdelivery device, the pump, and/or the oral liquid impermeable reservoirare removed from the mouth; (b) the drug delivery device, the pump,and/or the oral liquid impermeable reservoir are disconnected from thefastener; or (c) the oral liquid impermeable reservoir is disconnectedfrom the pump. In particular embodiments, the drug delivery device canbe configured to be automatically started upon one or more of thefollowing: (a) the drug delivery device, the pump, and/or the oralliquid impermeable reservoir are inserted into the mouth; (b) the drugdelivery device, the pump, and/or the oral liquid impermeable reservoirare connected to the fastener; or (c) the oral liquid impermeablereservoir is connected to the pump. In certain embodiments, theautomatic stop/start is selected from: a pressure sensitive switch, aclip, a fluidic channel that kinks, a clutch, a sensor, or a cap. Insome embodiments, the drug delivery device can further include asuction-induced flow limiter, a temperature-induced flow limiter,bite-resistant structural supports, or a pressure-invariant mechanicalpump.

In yet another aspect, the invention features a drug delivery deviceconfigured to be removably inserted in a patient's mouth and forcontinuous or semi-continuous intraoral administration of a drug, thedevice including: (i) a fastener to removably secure the drug deliverydevice to a surface of the patient's mouth; (ii) a mechanical pump;(iii) an oral liquid impermeable drug reservoir containing any of thepharmaceutical compositions of the invention, the volume of the drugreservoir being from 0.1 mL to 5 mL (e.g., as described herein); and(iv) a suction-induced flow limiter.

In some embodiments, the suction-induced flow limiter includespressurized surfaces that are in fluidic (gas and/or liquid) contactwith the ambient atmosphere via one or more ports or openings in thehousing of the drug delivery device. In other embodiments, thesuction-induced flow limiter is selected from the group consisting of adeformable channel, a deflectable diaphragm, a compliant accumulator, aninline vacuum-relief valve, and a float valve. In certain embodiments,the suction-induced flow limiter can be configured to prevent thedelivery of a bolus greater than about 1% (e.g., 2%, 3%, 4%, 5%, ormore) of the contents of a fresh drug reservoir, when the ambientpressure drops by 0.14 bar for a period of one minute. In someembodiments, the drug delivery device further includes an automaticstop/start, a temperature-induced flow limiter, bite-resistantstructural supports, or a pressure-invariant mechanical pump.

In another aspect, the invention features a drug delivery deviceconfigured to be removably inserted in a patient's mouth and forcontinuous or semi-continuous intraoral administration of a drug, thedevice including: (i) a fastener to removably secure the drug deliverydevice to a surface of the patient's mouth; (ii) an electrical ormechanical pump; (iii) an oral liquid impermeable drug reservoircontaining any of the pharmaceutical compositions of the invention, thevolume of the drug reservoir being from 0.1 mL to 5 mL (e.g., asdescribed herein); and (iv) a temperature-induced flow limiter.

In some embodiments, the temperature-induced flow limiter can includeinsulation with a material of low thermal conductivity proximate thedrug reservoir and/or the pump. In certain embodiments, thetemperature-induced flow limiter can include an elastomer whose force ina fresh reservoir increases by less than 30% when the oral temperatureis raised from about 37° C. to about 55° C. for a period of one minute.In some embodiments, the pump can include a spring and thetemperature-induced flow limiter can include a spring configured toproduce a force in a fresh reservoir that increases by less than 30%(e.g., 25%, 20%, 15%, or less) when the oral temperature is raised fromabout 37° C. to about 55° C. for a period of one minute. In particularembodiments, the temperature-induced flow limiter can include a springincluding a 300 series stainless steel, titanium, Inconel, or austeniticNitinol. In certain embodiments, the pump can be gas-driven. It cancomprise an actuator actuated by the temperature decrease upon removalfrom the mouth, i.e., a temperature change actuated flow limiter. Itsliquefied or compressed gas can have a volume of less than about 40%(e.g., 35%, 30%, 25%, 20%, 10% or less) of the volume of thepharmaceutical composition in a fresh reservoir at 37° C. and about1.013 bar.

In some embodiments of any of the above drug delivery devices, thedevice includes a rigid metal housing containing the pharmaceuticalcomposition and the propellant. The rigid metal housing material caninclude titanium or a titanium alloy. In particular embodiments, thepharmaceutical composition and the propellant are separated by aflexible and/or deformable diaphragm comprising a metal. The flexibleand/or deformable diaphragm can include tin or silver. In otherembodiments, the pump can be propellant-driven and thetemperature-induced flow limiter can include a propellant having a vaporpressure that increases by less than about 80% (e.g., 70%, 60%, 50%,40%, 30%, 20%, or less) when the oral temperature is raised from about37° C. to about 55° C. for a period of about one minute. In someembodiments, the drug delivery device further includes a suction-inducedflow limiter, an automatic stop/start, bite-resistant structuralsupports, or a pressure-invariant mechanical pump.

In yet another aspect, the invention features a drug delivery deviceconfigured to be removably inserted in a patient's mouth and forcontinuous or semi-continuous intraoral administration of a drug, thedevice including: (i) a fastener to removably secure the drug deliverydevice to a surface of the patient's mouth; (ii) an electrical ormechanical pump; (iii) an oral liquid impermeable drug reservoircontaining any of the pharmaceutical compositions of the invention, thevolume of the drug reservoir being from 0.1 mL to 5 mL (e.g., asdescribed herein); and (iv) bite-resistant structural supports.

In some embodiments, the bite-resistant structural supports are selectedfrom: a housing that encapsulates the entire drug reservoir and pumpcomponents; posts; ribs; or a potting material. In particularembodiments, the drug delivery device further includes a suction-inducedflow limiter, an automatic stop/start, a temperature-induced flowlimiter, or a pressure-invariant mechanical pump.

In a further aspect, the invention features a drug delivery deviceconfigured to be removably inserted in a patient's mouth and forcontinuous or semi-continuous intraoral administration of a drug, thedevice including: (i) a fastener to removably secure the drug deliverydevice to a surface of the patient's mouth; (ii) a pressure-invariantmechanical pump; and (iii) an oral liquid impermeable drug reservoircontaining any of the pharmaceutical compositions of the invention, thevolume of the drug reservoir being from 0.1 mL to 5 mL (e.g., asdescribed herein).

In some embodiments, the pressure-invariant mechanical pump includespressurized surfaces that are in fluidic (gas and/or liquid) contactwith the ambient atmosphere, optionally via one or more ports oropenings in the housing of the drug delivery device. In certainembodiments, the pressure-invariant mechanical pump is configured tomaintain an internal pressure of greater than or equal to about 2 bar,about 3 bar, about 4 bar, about 6 bar, or about 8 bar. In someembodiments, the pressure-invariant mechanical pump is configured suchthat the average rate of drug delivery increases by less than about 20%(e.g., 15%, 10%, 5%, 2% or less) when the atmospheric pressure decreasesfrom about 0.898 bar to about 0.782 or from 1.013 bar to 0.898 bar;and/or decreases by less than about 20% (e.g., less than 15%, 10%, 5%,2%) when the atmospheric pressure increases from about 0.782 bar toabout 0.898 bar; and/or such that the average rate of drug deliverydecreases by less than about 20% (e.g., 15%, 10%, 5%, 2% or less) whenthe atmospheric pressure increases from about 0.898 bar to about 1.013bar. In particular embodiments, the drug delivery device furtherincludes a suction-induced flow limiter, an automatic stop/start, atemperature-induced flow limiter, or bite-resistant structural supports.

In another aspect, the invention features a drug delivery deviceconfigured to be removably inserted in a patient's mouth and forcontinuous or semi-continuous intraoral administration of a drug, thedevice including: (i) a fastener to removably secure the drug deliverydevice to a surface of the patient's mouth; (ii) a mechanical pump; and(iii) an oral liquid impermeable drug reservoir containing any of thepharmaceutical compositions of the invention, the volume of the drugreservoir being from 0.1 mL to 5 mL (e.g., as described herein).

In some embodiments, the mechanical pump is pressure-invariant. Incertain embodiments, the mechanical pump is driven by a spring, anelastomer, a compressed gas, or a propellant. In some embodiments, theoral liquid impermeable reservoir includes one or more of: metalreservoirs, plastic reservoirs, elastomeric reservoirs, metallic barrierlayers, valves, squeegees, baffles, rotating augers, rotating drums,propellants, pneumatic pumps, diaphragm pumps, hydrophobic materials,and hydrophobic fluids. In particular embodiments, the drug deliverydevice can be configured such that 4 hours after inserting a drugdelivery device including a fresh reservoir in a patient's mouth andinitiating the administration, less than 5%, 3%, or 1% by weight of anoriginally contained pharmaceutical composition in the reservoirincludes an oral liquid. In certain embodiments, the oral liquidimpermeable drug reservoir includes a fluidic channel in a spiralconfiguration. In some embodiments, the drug delivery device furtherincludes a suction-induced flow limiter, an automatic stop/start, atemperature-induced flow limiter, a pressure-invariant mechanical pump,or bite-resistant structural supports.

Certain drug delivery devices of the invention may feature an electricalpump. In some embodiments, an electrical pump is a piezoelectric pump oran electroosmotic pump. In particular embodiments, the electrical pumpis a piezoelectric pump that is configured to operate at a frequency ofless than about 20,000 Hz (e.g., 15,000 Hz, 10,000 Hz, 5,000 Hz, orless). In certain embodiments, the electrical pump includes a motor.

Any of the drug delivery devices of the preceding aspects may include amechanical pump. In some embodiments, the mechanical pump is anelastomeric drug pump. In particular embodiments, the elastomeric drugpump includes an elastomeric balloon, an elastomeric band, or acompressed elastomer. In other embodiments, the mechanical pump is aspring-driven pump. In particular embodiments, the spring-driven pumpincludes a constant force spring. In certain embodiments, thespring-driven pump includes a spring that retracts upon relaxation. Insome embodiments, the spring-driven pump includes two coaxialcompression springs wherein, upon compression, a first spring with afirst diameter is wholly or partially nested within a second spring witha second, larger diameter. In other embodiments, the mechanical pump isa negative pressure pump, a pneumatic pump, or a gas-driven pump. Incertain embodiments, the mechanical pump is a gas-driven pump includinga gas in a first compartment and drug in a second compartment, the gasproviding a pressure exceeding about 1 bar. In some embodiments, thegas-driven pump includes a compressed gas cartridge. In particularembodiments, the gas-driven pump includes a compressed or liquefied gas,the volume of the compressed or liquefied gas being less than 35% (e.g.,less than 30%, 25%, 20% or 10%) of the volume of the pharmaceuticalcomposition. In some embodiments, a gas-driven pump includes a gasgenerator.

In any of the preceding aspects, a drug delivery device may include amechanical pump that is a propellant-driven pump. In some embodiments,the pump includes a liquid propellant, the liquid propellant having aboiling point of less than 37° C. (e.g., less than or equal to 35° C.,33° C., 30° C., or 25° C.) at sea level atmospheric pressure. In certainembodiments, the liquid propellant is a hydrocarbon, a halocarbon, ahydrofluoralkane, an ester, or an ether. For example, the liquidpropellant can be selected from the group consisting of isopentane,trifluorochloromethane, dichlorofluoromethane, 1-fluorobutane,2-fluorobutane, 1,2-difluoroethane, methyl ethyl ether, 2-butene,butane, 1-fluoropropane, 1-butene, 2-fluoropropane, 1,1-difluoroethane,cyclopropene, propane, propene, or diethyl ether. In particularembodiments, the liquid propellant is 1,1,1,2-tetrafluoroethane,1,1,1,2,3,3,3-heptafluoropropane, 1,1,1,3,3,3-hexafluoropropane,octafluorocyclobutane, or isopentane. In certain embodiments, the liquidpropellant is isopentane, trifluorochloromethane, dichlorofluoromethane,or 1,1,1,2-tetrafluoroethane. In some embodiments, the liquid propellanthas a vapor pressure of greater than 1.5 bar (e.g., 2.0 bar, 2.5 bar, 3bar, or greater) and less than 20 bar (e.g., 15 bar, 12 bar, 10 bar, 9bar, 8 bar, 7.0 bar, 6.0 bar, or less) at about 37° C. In otherembodiments, (i) the liquid propellant has a vapor pressure of greaterthan 2.1 bar (e.g., greater than 2.2 bar, 2.5 bar, or 3.0 bar) at 37°C., and (ii) the average rate of drug delivery increases or decreases byless than ±20% across the atmospheric pressure range between about 0.782bar and about 1.013 bar. In particular embodiments, (i) the liquidpropellant has a vapor pressure of greater than 3.2 bar (e.g., greaterthan 3.3 bar, 3.4 bar, or 3.5 bar) at 37° C., and (ii) the average rateof drug delivery increases or decreases by less than ±10% across theatmospheric pressure range between about 0.782 bar and about 1.013 bar.In further embodiments, (i) the propellant has a vapor pressure ofgreater than 4.7 bar (e.g., 4.8 bar, 5.0 bar, or greater) at 37° C., and(ii) the average rate of drug delivery increases or decreases by lessthan ±6% across the atmospheric pressure range between about 0.782 barand about 1.013 bar.

In any of the preceding aspects of the invention, a drug delivery devicemay include two or more drug pumps. A drug delivery device may alsoinclude two or more drug reservoirs.

In any of the preceding aspects of the invention, a drug reservoir maybe substantially impermeable to oxygen gas. In certain embodiments, thedrug reservoir includes a pharmaceutical composition comprising greaterthan 33% (e.g., greater than 35%, greater than 37%, greater than 39%,greater than 40%, greater than 50%, greater than 60%, or more) of thetotal volume of the drug reservoir and pump. In some embodiments, thetotal volume of the one or more drug reservoirs and the one or more drugpumps is less than 5 mL (e.g., less than 4 mL, less than 3 mL, less than2 mL, or less than 1 mL).

In some embodiments, the drug reservoir of a drug delivery device of theinvention is a syringe assembly including a plunger and a barrel, theplunger being in slidable arrangement with the barrel. In certainembodiments, the syringe assembly further includes a seal (e.g., anO-ring) fitted over the plunger, the seal being in contact with thebarrel. In some embodiments, the barrel, plunger, and/or seal is notwetted by water and/or oil. In particular embodiments, the barrel,plunger, and/or seal is non-wettable by a pharmaceutical composition ofthe invention. In some embodiments, a barrel, plunger, and/or seal isformed from or coated with a fluoropolymer or fluoroelastomer. Incertain embodiments, a barrel, plunger, and/or seal is coated with alubricant. The solubility of the lubricant in the one or morewater-immiscible compounds of the pharmaceutical composition may be lessthan 3% (w/w) (e.g., less than 2% (w/w) or less than 1% (w/w)) at, forexample, 25° C. In some embodiments, the lubricant can be a halogenatedoil or grease, such as a perfluorinated polymer, a chlorofluorinatedpolymer, or a fluorinated polyether. In certain embodiments, thelubricant can be a halogenated oil or grease having an average molecularmass equal to or greater than about 1,000 Daltons (e.g., greater thanabout 1,100 Daltons, greater than about 1,200 Daltons, greater thanabout 1,500 Daltons, greater than about 1,700 Daltons, or greater thanabout 2,000 Daltons). In some embodiments, the drug reservoir of a drugdelivery device can be a syringe barrel and the drug delivery device canfurther include a deformable and/or mobile plug separating twocompartments of the syringe barrel. In certain embodiments, thedeformable and/or mobile plug includes a perfluorinated, fluorinated, orchlorofluorinated oil or grease. Such a drug delivery device may furtherinclude a propellant in one of the compartments and the pharmaceuticalcomposition in the other of the compartments.

A drug delivery device of the invention may removably secure to one ormore teeth of the patient. In some embodiments, the fastener thatremovably secures the drug delivery device to one or more teeth includesa band, a bracket, a clasp, a splint, or a retainer. For example, thefastener may include a transparent retainer or a partial retainerattachable to fewer than 5 teeth.

A drug delivery device of the invention may include one or more drugreservoirs and one or more pumps configured to be worn in the buccalvestibule, on the lingual side of the teeth, or simultaneously in thebuccal vestibule and on the lingual side of the teeth. In someembodiments, one or more drug reservoirs and one or more pumps areconfigured bilaterally. In certain embodiments, the one or more drugreservoirs and/or pumps are configured to administer the pharmaceuticalcomposition into the mouth of the patient on the lingual side of theteeth. A fluidic channel from the buccal side to the lingual side of thepatient's teeth may be included for dispensing the pharmaceuticalcomposition. In one particular embodiment of any of the above drugdelivery devices, the device includes one or more drug reservoirs andone or more pumps, wherein the drug reservoirs or the pumps areconfigured to administer the pharmaceutical composition onto the buccalor sublingual mucosa of the patient. For example, the drug deliverydevice can include a tube, channel, or orifice having a distal endpositioned proximal to the buccal or sublingual mucosa within a zonebounded in part by a water vapor and gas permeable membrane that issaliva-repelling. In some embodiments, the drug delivery device caninclude a fluidic channel in the fastener through which thepharmaceutical composition is administered into the mouth of thepatient. In certain embodiments, the device may include a leak-freefluidic connector for direct or indirect fluidic connection of thefastener to the one or more drug reservoirs, and/or a flow restrictor inthe fastener for controlling the flow of the pharmaceutical composition.In some embodiments, the fastener includes a pump or a power source.

In particular embodiments, the drug delivery device includes one or moredrug metal wall including reservoirs and one or more pumps, wherein thedrug reservoirs or the pumps are configured to administer thepharmaceutical composition onto the buccal or sublingual mucosa of thepatient. The drug delivery device can include a tube, channel, ororifice having a distal end positioned proximal to the buccal orsublingual mucosa within a zone bounded in part by a water vapor and gaspermeable membrane that is saliva-repelling.

In some embodiments, the drug reservoir of a drug delivery device of theinvention is in fluid communication with a tube, channel, or orifice ofless than 4 cm (e.g., less than 3 cm, less than 2 cm, less than 1 cm,less than 0.5 cm, or less than 0.2 cm) in length and the dynamicviscosity of the pharmaceutical composition can be greater than about1,000 cP (e.g., greater than about 5,000 cP, greater than about 10,000cP, greater than about 50,000 cP, or greater than about 100,000 cP), andthe device is configured to administer drug via the tube, channel, ororifice. In certain embodiments, the tube, channel, or orifice has aminimum internal diameter of greater than about 0.2 mm, e.g., greaterthan about 0.3 mm, greater than about 0.4 mm, greater than about 0.5 mm,greater than about 0.6 mm, greater than about 0.7 mm, greater than about1 mm, greater than about 2 mm, greater than about 3 mm, greater thanabout 4 mm, greater than about 5 mm, or greater than about 6 mm. Incertain embodiments, the internal diameter is greater than about 0.1 mmand less than 1 mm, 0.8 mm, 0.6 mm, 0.5 mm, 0.4 mm, 0.3 mm or 0.2 mm.Preferred minimum internal diameters are 0.1-2 mm (0.1-0.7 mm, 0.2-0.5mm, 0.5-0.75 mm, 0.75-1.0 mm, 1.0-1.5 mm, or 1.5-2.0 mm) and preferredlengths are 0.25-5 cm (such as 1-2.5 cm, 1-5 cm, 0.25-0.5 cm, 0.5-0.75cm, 0.75-1 cm, 1-2 cm, 2-3 cm, 3-4 cm, or 4-5 cm).

In some embodiments, a drug delivery device of the invention furtherincludes a flow restrictor (e.g., a flared flow restrictor). The flowrestrictor can have an internal diameter smaller than 1 mm and largerthan 0.05 mm and a length between 0.5 cm and 10 cm. In particularembodiments, the flow restrictor can have an internal diameter smallerthan 0.7 mm and larger than 0.2 mm. Preferred minimum internal diametersare 0.1-2 mm (0.1-0.7 mm, 0.2-0.5 mm, 0.5-0.75 mm, 0.75-1.0 mm, 1.0-1.5mm, or 1.5-2.0 mm) and preferred lengths are 0.25-5 cm (such as 1-2.5cm, 1-5 cm, 0.25-0.5 cm, 0.5-0.75 cm, 0.75-1 cm, 1-2 cm, 2-3 cm, 3-4 cm,or 4-5 cm). The flow restrictor can be made of a plastic, such as anengineering plastic. In particular embodiments, the engineering plasticincludes a polyamide or a polyester, or a polycarbonate, or apolyetheretherketone, or a polyetherketone, or a polyimide, or apolyoxymethylene, or a polyphenylene sulfide, or a polyphenylene oxide,or a polysulphone, or polytetrafluoroethylene, or polyvinylidenedifluoride, or ultra-high-molecular-weight polyethylene, or a strongelastomer.

In certain embodiments, the flow restrictor controls the flow of thepharmaceutical composition. In some embodiments, the length of the flowrestrictor sets the administration rate of the pharmaceuticalcomposition. In particular embodiments, the flow restrictor may beadjusted by a physician or the patient to set the rate of flow. Incertain embodiments, a drug delivery device can include a tapered flowpath for the drug with a taper less than or equal to about 60 degrees,about 45 degrees, or about 30 degrees. Optionally, the device caninclude one or more flow-controlling nozzles, channels or tubes whichcan be plastic, e.g. made of or including an engineering plastic. Theoptionally plastic nozzles, channels or tubes can have an internaldiameter less than 1 mm, 0.6 mm, 0.3 mm or 0.1 mm and they can beshorter than 10 cm, 5 cm, 2 cm or 1 cm such as 0.5 cm. Preferred minimuminternal diameters are 0.1-2 mm (0.1-0.7 mm, 0.2-0.5 mm, 0.5-0.75 mm,0.75-1.0 mm, 1.0-1.5 mm, or 1.5-2.0 mm) and preferred lengths are 0.25-5cm (such as 1-2.5 cm, 1-5 cm, 0.25-0.5 cm, 0.5-0.75 cm, 0.75-1 cm, 1-2cm, 2-3 cm, 3-4 cm, or 4-5 cm).

Any of the drug delivery devices of the invention may be configured todeliver an average hourly rate of volume of from about 0.015 mL/hour toabout 1.25 mL/hour (e.g., from about 0.015 mL/hour to about 1.20mL/hour, from about 0.015 mL/hour to about 1.15 mL/hour, from about0.015 mL/hour to about 1.10 mL/hour, from about 0.015 mL/hour to about1.05 mL/hour, from about 0.015 mL/hour to about 1.00 mL/hour, from about0.015 mL/hour to about 0.90 mL/hour, from about 0.015 mL/hour to about0.80 mL/hour, from about 0.015 mL/hour to about 0.70 mL/hour, from about0.015 mL/hour to about 0.60 mL/hour, from about 0.015 mL/hour to about0.50 mL/hour, from about 0.015 mL/hour to about 0.25 mL/hour, from about0.015 mL/hour to about 0.10 mL/hour, from about 0.015 mL/hour to about0.05 mL/hour, from about 0.015 mL/hour to about 0.025 mL/hour, fromabout 0.015 mL/hour to about 0.020 mL/hour, from about 0.020 mL/hour toabout 1.25 mL/hour, from about 0.025 mL/hour to about 1.25 mL/hour, fromabout 0.050 mL/hour to about 1.25 mL/hour, from about 0.075 mL/hour toabout 1.25 mL/hour, from about 0.10 mL/hour to about 1.25 mL/hour, fromabout 0.20 mL/hour to about 1.25 mL/hour, from about 0.50 mL/hour toabout 1.25 mL/hour, from about 0.75 mL/hour to about 1.25 mL/hour, fromabout 1.00 mL/hour to about 1.25 mL/hour, from about 1.10 mL/hour toabout 1.25 mL/hour, from about 1.15 mL/hour to about 1.25 mL/hour, fromabout 0.25 mL/hour to about 0.50 mL/hour, from about 0.5 mL/hour toabout 0.75 mL/hour, or from about 0.75 mL/hour to about 1.0 mL/hour)over a period of from about 4 hours to about 168 hours (e.g., from about4 hours to about 120 hours, from about 4 hours to about 100 hours, fromabout 4 hours to about 80 hours, from about 4 hours to about 72 hours,from about 4 hours to about 60 hours, from about 4 hours to about 48hours, from about 4 hours to about 36 hours, from about 4 hours to about24 hours, from about 4 hours to about 12 hours from about 4 hours toabout 8 hours, from about 4 hours to about 6 hours, from about 6 hoursto about 168 hours, from about 8 hours to about 168 hours, from about 12hours to about 168 hours, from about 24 hours to about 168 hours, fromabout 36 hours to about 168 hours, from about 48 hours to about 168hours, from about 60 hours to about 168 hours, or from about 72 hours toabout 168 hours) at about 37° C. and a constant pressure of about 1.013bar, wherein the average hourly rate varies by less than ±20% or ±10%per hour over a period of 4 or more hours (e.g., 6 hours, 8 hours, 10hours, 12 hours, 18 hours, 24 hours, 36 hours, 48 hours, 60 hours, 72hours, 168 hours, or more). In some embodiments, the drug deliverydevice can include oral fluid contacting surfaces that are compatiblewith the oral fluids, such that the average rate of delivery of the drugincreases or decreases by less than ±20% or ±10% per hour after the drugdelivery device is immersed for five minutes in a stirred physiologicalsaline solution at 37° C. including any one of the following conditions:(a) pH of about 2.5; (b) pH of about 9.0; (c) 5% by weight olive oil;and (d) 5% by weight ethanol.

The invention also features a method of treating Parkinson's disease(including patients with scores of 4 and 5 on the Hoehn and Yahr scale)including administering a pharmaceutical composition of the invention toa patient using a drug delivery device of the invention.

In another aspect, the invention features a method of administering apharmaceutical composition to a patient, the method including removablyattaching a drug delivery device of the invention to an intraoralsurface of the patient. In certain embodiments, the method furtherincludes detaching the device from the intraoral surface and/oradministering drug to the patient for a delivery period of not less thanabout 4 hours and not more than about 7 days. In some embodiments, thedrug delivery device includes a drug reservoir including a volume of adrug, and the method further includes oral administration at a rate inthe range of from 15 μL per hour to about 1.25 mL per hour (e.g., asdescribed herein) during the delivery period. In particular embodiments,the fluctuation index of the drug is less than or equal to 2.0, 1.5,1.0, 0.75, 0.50, 0.25, or 0.15 during the delivery period. In someembodiments, the drug delivery device can include a drug reservoirincluding a pharmaceutical composition including a drug and the drug isadministered to the patient at an average rate of not less than 0.01 mgper hour and not more than 125 mg per hour (e.g., from about 0.01mg/hour to about 125 mg/hour, from about 0.05 mg/hour to about 125mg/hour, from about 0.10 mg/hour to about 125 mg/hour, from about 0.50mg/hour to about 125 mg/hour, from about 1.0 mg/hour to about 125mg/hour from about 5.0 mg/hour to about 125 mg/hour, from about 10mg/hour to about 125 mg/hour, from about 25 mg/hour to about 125mg/hour, from about 50 mg/hour to about 125 mg/hour, from about 100mg/hour to about 125 mg/hour, from about 0.01 mg/hour to about 100mg/hour, from about 0.01 mg/hour to about 50 mg/hour, from about 0.01mg/hour to about 25 mg/hour, from about 0.01 mg/hour to about 10mg/hour, from about 0.01 mg/hour to about 5.0 mg/hour, from about 0.01mg/hour to about 1.0 mg/hour, from about 0.01 mg/hour to about 0.5mg/hour, from about 0.01 mg/hour to about 0.25 mg/hour, from about 0.01mg/hour to about 0.1 mg/hour, from about 0.01 mg/hour to about 0.05mg/hour, or from about 1 mg/hour to about 10 mg/hour, from about 10mg/hour to about 100 mg/hour). In some embodiments, the pharmaceuticalcomposition can be administered to the patient at least once every 60minutes, at least once every 30 minutes, or at least once every 15minutes. In other embodiments, the pharmaceutical composition isadministered to the patient continuously. In certain embodiments, thepharmaceutical composition can be administered to the patient over adelivery period of about 8 or more hours (e.g., more than 10, 12, 14,16, 18, 20, or 24 hours).

In certain embodiments, a method of administering a pharmaceuticalcomposition of the invention further includes treating a disease in thepatient, wherein the disease is spasticity, muscle weakness, mucositis,allergy, immune disease, anesthesia, bacterial infections, cancer, pain,organ transplantation, disordered sleep, epilepsy and seizures, anxiety,mood disorders, post-traumatic stress disorder, arrhythmia,hypertension, heart failure, or diabetic nephropathy.

In one particular embodiment of any of the above methods, the methodfurther includes treating a disease in the patient, wherein the diseaseis multiple sclerosis, cerebral palsy, spasticity, neurogenicorthostatic hypotension, Wilson's disease, cystinuria, rheumatoidarthritis, Alzheimer's disease, myasthenia gravis, Type-1 Gaucherdisease, Type C Niemann-Pick disease, eosinophilic gastroenteritis,chronic mastocytosis, ulcerative colitis, gastro-oesophageal reflux,gastroenteritis, hyperemesis gravidarum, glioblastoma multiformae,anaplastic astrocytoma, pulmonary hypertension, coronary heart diseasecongestive heart failure, angina, Type 2 diabetes, COPD, asthma,irritable bowel syndrome, overactive bladder, and urinary urgeincontinence. In one particular embodiment, the method includes treatingmyasthenia gravis and the pharmaceutical composition includespyridostigmine, or a pharmaceutically acceptable salt thereof.

In one particular embodiment, the pharmaceutical composition includesone or more drugs selected from methylphenidate, prostaglandins,prostacyclin, treprostinil, beraprost, nimodipine, and testosterone. Instill other embodiments, the pharmaceutical composition includes amucoadhesive polymer. The pharmaceutical composition can further includea permeation enhancer. In particular embodiments of any of the abovemethods, the pharmaceutical composition can include drug dissolved in anaqueous solution. The aqueous solution can optionally further includeglycerol, ethanol, propylene glycol, polyethylene glycol (PEO, PEG) orDMSO. In still other embodiments, the pharmaceutical composition furtherincludes a thickening agent (e.g., a sugar, a sugar alcohol, or apolymer, such as cellulose or a cellulose derivative). In particularembodiments, the thickening agent is selected from carboxymethylcellulose, microcrystalline cellulose, hyaluronic acid, polyacrylicacid, polymethacrylic acid, alginic acid, or salts thereof. In stillother embodiments, the thickening agent is selected from sucrose,glucose, fructose, sorbitol, and mannitol.

In any of the methods of the invention, the pharmaceutical compositionmay include one or more of methylphenidate, prostaglandins,prostacyclin, treprostinil, beraprost, nimodipine, and testosterone.

In any of the preceding embodiments of the above compositions andmethods, the pharmaceutical composition may include a mucoadhesivepolymer and, optionally, a permeation enhancer (e.g., to aid transportacross the sublingual or buccal mucosa).

In any of the preceding embodiments of the above compositions andmethods, the pharmaceutical composition may include drug dissolved in anaqueous solution. The aqueous solution can further include glycerol,ethanol, propylene glycol, polyethylene glycol (PEO, PEG) or DMSO (e.g.,from 0.5% (w/w) to 20% (w/w)).

In any of the preceding embodiments of the above compositions andmethods, the pharmaceutical composition may further include aviscosity-increasing agent (e.g., a dissolved sugar or sugar alcoholsuch as one selected from sucrose, glucose, fructose, sorbitol, andmannitol, or a dissolved polymer, or water-swollen polymer, or a gelforming polymer, such one selected from carboxymethyl cellulose,hyaluronic acid, polyacrylic acid, polymethacrylic acid, alginic acid,or salts thereof. Alternatively, it can be an undissolved viscosityincreasing thickening agent. In particular embodiments, the thickeningagent is a cellulose, such as a non-swelling cellulose derivative; or acellulose derivative, or an undissolved polymer selected fromcarboxymethyl cellulose, hyaluronic acid, polyacrylic acid,polymethacrylic acid, alginic acid, or salts thereof, or a solid aminoacid, like tyrosine or phenylalanine.

In any of the methods of the invention, the method may further includetreating Parkinson's disease (including patients with scores of 4 and 5on the Hoehn and Yahr scale), wherein the pharmaceutical compositionincludes levodopa or a levodopa prodrug.

The invention also features a method for treating Parkinson's disease ina patient (including patients with scores of 4 and 5 on the Hoehn andYahr scale), the method including: (a) inserting a drug delivery deviceof the invention into the patient's mouth, the device having a drugreservoir including levodopa or a levodopa prodrug; (b) administeringinto the patient's mouth the levodopa or a levodopa prodrug for a periodof at least 4, 6, or 8 hours (e.g., as described herein) at an hourlyrate in the range of 30 mg/hour to 150 mg/hour (e.g., as describedherein, such as 50 mg/hour to 125 mg/hour), such that a circulatingplasma levodopa concentration greater than 1,200 ng/mL (e.g., greaterthan 1,400 ng/mL, 1,500 ng/mL, 1,600 ng/mL, 1,800 ng/mL, 2,000 ng/mL, or2,200 ng, mL) and less than 2,500 ng/mL (e.g., less than 2,200 ng/mL,2,000 ng/mL, 1,800 ng/mL, 1,600 ng/mL, or 1,400 ng/mL) is continuouslymaintained for a period of at least 4, 6, or 8 hours (e.g., as describedherein) during the administration; and (c) removing the drug deliverydevice from the mouth.

In another aspect, the invention features a method for treatingParkinson's disease in a patient (including patients with scores of 4and 5 on the Hoehn and Yahr scale), the method including: (a) insertinga drug delivery device including a pharmaceutical composition of theinvention into the patient's mouth, the pharmaceutical compositionincluding levodopa or levodopa prodrug; (b) administering into thepatient's mouth the levodopa or levodopa prodrug for a period of atleast 4, 6, or 8 hours (e.g., as described herein) at an hourly rate inthe range of 30 mg/hour to 150 mg/hour (e.g., as described herein, suchas 50 mg/hour to 125 mg/hour), such that a circulating plasma levodopaconcentration greater than 1,200 ng/mL (e.g., as described herein) andless than 2,500 ng/mL (e.g., as described herein) is continuouslymaintained for a period of at least 4, 6, or 8 hours (e.g., as describedherein) during the administration; and (c) removing the drug deliverydevice from the mouth.

In a method for treating Parkinson's disease in a patient (includingpatients with scores of 4 and 5 on the Hoehn and Yahr scale), thefluctuation index of levodopa may be less than or equal to 2.0, 1.5,1.0, 0.75, 0.50, 0.25, or 0.15 for a period of at least 4 hours (e.g.,at least 6 hours, at least 8 hours, or longer) during theadministration. In some embodiments, during administration thecirculating levodopa plasma concentration varies by less than +/−20% or+/−10% from its mean for a period of at least 1 hour (e.g., 2 hours, 3hours, 4 hours, or more hours).

In a further aspect, the invention features a method for treatingParkinson's disease in a patient (including patients with scores of 4and 5 on the Hoehn and Yahr scale), the method including continuous orsemi-continuous administration of a pharmaceutical composition of theinvention into the patient at a rate of 10 mg/hour to 200 mg/hour (e.g.,as described herein, such as 30 mg/hour to 150 mg/hour or 50 mg/hour to125 mg/hour) for a period of about 4 hours to about 168 hours (e.g., asdescribed herein).

In some embodiments of methods of treating Parkinson's disease, thepatient has a motor or non-motor complication of Parkinson's diseasesuch as a complication including tremor, akinesia, bradykinesia,dyskinesia, dystonia, cognitive impairment, or disordered sleep. Inparticular embodiments, the method of treating Parkinson's diseaseincludes treating a motor or non-motor complication of Parkinson'sdisease.

The invention also features a method of treating Parkinson's disease(including patients with scores of 4 and 5 on the Hoehn and Yahr scale)in a patient including administering a pharmaceutical composition of theinvention to a patient using the methods described herein.

In a further aspect, the invention features a method of preparing apharmaceutical composition including from about 35% (w/w) to about 70%(w/w) of a drug including levodopa and/or carbidopa; the pharmaceuticalcomposition including a surfactant, an oil, and water; thepharmaceutical composition, when at 37° C., including solid particles ofdrug; the drug having a partition coefficient in favor of water; thesurfactant being present in an amount sufficient to render thecomposition physically stable; and the method including contacting anaqueous solution including the surfactant and water with solid particlesof the drug, to produce a mixture of solid particles in aqueoussolution. The method may further include contacting the mixture with theoil.

In embodiments featuring delivery across the buccal mucosa, theinvention further includes delivering the drug-containing compositioninto a location in the mouth such that the drug has a residence time ator near the mucosa of greater than 2 minutes, 5 minutes, 10 minutes, 30minutes, or 60 minutes before being removed from contact with the oralmucosa (e.g., by saliva-dilution and/or swallowing). Several techniquesand device configurations may be used to obtain the desired residencetime, optionally in combination with each other. In one embodiment, thedrug-containing composition is delivered into a portion of the mouthwhere the flux of saliva is slow, e.g., into the cheek pocket betweenthe bottom teeth/gums and the cheek, and preferably not proximate asalivary gland. In a related embodiment, the composition may bemucoadhesive or include a mucoadhesive to retain the drug proximate themucosa. In yet another related embodiment, the drug-containingcomposition may be delivered into a material that retains the drugproximate the mucosa, such as a sorbent.

In a related aspect, the invention features a method for treatingParkinson's disease in a subject, the method including: (a) inserting adrug delivery device into the subject's mouth, the device having (i) afastener to removably secure the drug delivery device to a surface ofthe patient's mouth; (ii) an electrical or mechanical pump; and (iii) anoral liquid impermeable drug reservoir having a volume of from 0.1 ml to5 ml including a suspension or solid containing levodopa or a levodopaprodrug; (b) administering into the patient's mouth the levodopa or alevodopa prodrug continuously or semi-continuously; and (c) removing thedrug delivery device from the mouth of the subject, wherein the subjecthas a score of 4 and 5 on the Hoehn and Yahr scale. In some embodiments,step (b) includes administering into the subject's mouth the levodopa ora levodopa prodrug semi-continuously at a frequency of at least onceevery 30 minutes. In certain embodiments, the suspension or solid isadministered to the subject for a period of at least 8 hours at anhourly rate in the range of 10-125 mg/hour, such that a circulatingplasma levodopa concentration greater than 1,200 ng/m L and less than2,500 ng/mL is continuously maintained for a period of at least 8 hoursduring the administration.

In one particular embodiment, the subject can have delayed gastricemptying or retarded gastrointestinal transit, e.g., induced byLD-derived dopamine, the dopamine being formed by decarboxylation of LD(e.g., in the mesentery of the gastrointestinal tract).

In still other embodiments, the drug reservoir includes a compositionincluding a suspension that is a drug particle-containing emulsionincluding (i) from 35% to 70% (w/w) drug particles including levodopaand/or carbidopa, or salts thereof, (ii) from 19% to 30% (w/w) of one ormore water-immiscible compounds, (iii) from 2% to 16% (w/w) water, and(iv) from 1% to 8% (w/w) surfactant. The suspension can include acontinuous hydrophilic phase including greater than 50% (w/w) drugparticles. Optionally, the drug delivery device includes an automaticstop/start, a suction-induced flow limiter, a temperature-induced flowlimiter, and/or bite-resistant structural supports.

In a related aspect, the invention features a method for treatingspasticity in a subject, the method including: (a) inserting a drugdelivery device into the subject's mouth, the device having (i) afastener to removably secure the drug delivery device to a surface ofthe patient's mouth; (ii) an electrical or mechanical pump; and (iii) anoral liquid impermeable drug reservoir having a volume of from 0.1 ml to5 ml including a suspension or solid containing baclofen or apharmaceutically acceptable salt thereof; (b) administering into thepatients mouth the baclofen continuously or semi-continuously; and (c)removing the drug delivery device from the mouth of the subject.

In a related aspect, the invention features a method for treatingmyasthenia gravis in a subject, the method including: (a) inserting adrug delivery device into the subjects mouth, the device having (i) afastener to removably secure the drug delivery device to a surface ofthe patient's mouth; (ii) an electrical or mechanical pump; and (iii) anoral liquid impermeable drug reservoir having a volume of from 0.1 ml to5 ml including a solution or suspension of pyridostigmine or apharmaceutically acceptable salt thereof; (b) administering into thepatient's mouth the pyridostigmine continuously or semi-continuously;and (c) removing the drug delivery device from the mouth of the subject.

In an embodiment of any of the above devices, methods, andpharmaceutical compositions, the drug can be an analgesic (e.g.,lidocaine, bupivacaine, mepivacaine, ropivacaine, tetracaine,etidocaine, chloroprocaine, prilocaine, procaine, benzocaine, dibucaine,dyclonine hydrochloride, pramoxine hydrochloride, benzocaine,proparacaine, and their pharmaceutically acceptable salts) or an opioid(e.g., buprenorphine, nor-buprenorphine, fentanyl, methadone,levorphanol, morphine, hydromorphone, oxymorphone codeine, oxycodone,hydrocodone, and their pharmaceutically acceptable salts) administeredfor the treatment of pain.

The invention features a method for treating disease in a subjectsuffering from delayed gastric emptying or retarded gastrointestinaltransit, the method including: (a) inserting a drug delivery device intothe subject's mouth, the device having (i) a fastener to removablysecure the drug delivery device to a surface of the patients mouth; (ii)an electrical or mechanical pump; and (iii) an oral liquid impermeabledrug reservoir having a volume of from 0.1 ml to 5 ml including asuspension or solid containing a drug useful for treating the disease;(b) administering into the patients mouth the drug continuously orsemi-continuously at a frequency of at least once every 30 minutes; and(c) removing the drug delivery device from the mouth of the subject. Inparticular embodiments, an efficacious circulating plasma concentrationof the drug is continuously maintained for a period of at least 8 hoursduring the administration. The drug delivery device can include anautomatic stop/start, a suction-induced flow limiter, atemperature-induced flow limiter, and/or bite-resistant structuralsupports.

The invention features a drug delivery device configured forcontinuously or semi-continuously administering a drug into the mouth ofa patient, the drug delivery device including: a pharmaceuticalcomposition including a paste, solution or suspension having a viscositygreater than 100 poise and less than 500,000 poise at 37° C. andincluding the drug; and a mechanical pump including a flow restrictor,the flow restrictor including an internal diameter between 0.05 mm and3.00 mm and a length between 0.25 cm and 20 cm, configured and arrangedto administer the pharmaceutical composition at a rate between 0.001mL/hour and 1.25 mL/hour. The mechanical pump can include a propellant.In particular embodiments, the propellant has a vapor pressure at about37° C. greater than 1.2 bar and less than 50 bar. The pharmaceuticalcomposition includes solid drug particles and/or excipient particles canhave a D₉₀ between 0.1 μm and 200 μm and a D₅₀ between 0.1 μm and 50 μmwhen measured by light scattering with the particles dispersed in anon-solvent. The drug delivery device of can be configured such that:(i) the administration rate is greater than 0.03 mL/hour and less than0.5 mL/hour; (ii) the viscosity greater than 200 poise and less than100,000 poise; (iii) the flow restrictor has an internal diameterbetween 0.1 mm and 0.7 mm and a length between 1 cm and 5 cm; and (iv)the propellant has a vapor pressure at about 37° C. greater than 2.5 barand less than 15 bar. In particular embodiments, the solid drugparticles and/or excipient particles having a D₉₀ between 1 μm and 50 μmand a D₅₀ between 0.5 μm and 30 μm when measured by light scatteringwith the particles dispersed in a non-solvent. The drug delivery deviceof can be configured such that: (i) the administration rate is greaterthan 0.05 mL/hour and less than 0.2 mL/hour; (ii) the viscosity isgreater than 500 poise and less than 75,000 poise; (iii) the flowrestrictor has an internal diameter between 0.2 mm and 0.5 mm and alength between 1 cm and 2.5 cm; and (iv) the propellant has a vaporpressure at about 37° C. greater than 4 bar and less than 10 bar. Inparticular embodiments, the solid drug particles and/or excipientparticles having a D₉₀ between 3 μm and 30 μm and a D₅₀ between 2 μm and20 μm when measured by light scattering with the particles dispersed ina non-solvent.

The invention further features a method of administering apharmaceutical composition to a patient, the method including: (i)inserting the drug delivery device into the mouth of the patient; (ii)continuously or semicontinuously administering the pharmaceuticalcomposition into the mouth of a patient using at a rate between 0.001mL/hour and 1.25 mL/hour; (iii) wherein the pharmaceutical compositionincludes a paste, solution or suspension having a viscosity greater than100 poise and less than 500,000 poise at 37° C.; and (iv) the drugdelivery device includes a mechanical pump including a flow restrictorincluding an internal diameter between 0.05 mm and 3.00 mm and a lengthbetween 0.25 cm and 20 cm. In certain embodiments, the mechanical pumpincludes a propellant, the propellant having a vapor pressure at about37° C. greater than 1.2 bar and less than 50 bar. The solid drugparticles and/or excipient particles can have a D₉₀ between 0.1 μm and200 μm and a D₅₀ between 0.1 μm and 50 μm when measured by lightscattering with the particles dispersed in a non-solvent. In certainembodiments, the administration rate is greater than 0.03 mL/hour andless than 0.5 mL/hour; the viscosity greater than 200 poise and lessthan 100,000 poise; the flow restrictor having an internal diameterbetween 0.1 mm and 0.7 mm and a length between 1 cm and 5 cm; and thepropellant has a vapor pressure at about 37° C. greater than 2.5 bar andless than 15 bar. The solid drug particles and/or excipient particlescan have a D₉₀ between 0.1 μm and 50 μm and a D₅₀ between 0.5 μm and 30μm when measured by light scattering with the particles dispersed in anon-solvent. In particular embodiments, the administration rate isgreater than 0.05 mL/hour and less than 0.2 mL/hour; the viscosity isgreater than 500 poise and less than 75,000 poise; the flow restrictorhas an internal diameter between 0.2 mm and 0.5 mm and a length between1 cm and 2.5 cm; and the propellant has a vapor pressure at about 37° C.greater than 4 bar and less than 10 bar. The solid drug particles and/orexcipient particles can have a D₉₀ between 3 μm and 30 μm and a D₅₀between 2 μm and 20 μm when measured by light scattering with theparticles dispersed in a non-solvent.

ABBREVIATIONS AND DEFINITIONS

The term “about,” as used herein, refers to a number that is ±10% of avalue that this term precedes except when the value is that of atemperature. For temperatures “about” means±3° C.

The term “administration” or “administering” refers to a method ofgiving a dosage of a therapeutic drug, such as LD and/or carbidopa (CD),to a patient. The drug may be formulated as a fluid, such as a viscoussuspension. Fluids may be infused. The dosage form of the invention ispreferably administered into the mouth or nasal cavity, optionally usinga drug delivery device such as an infusion pump, and the drug can beswallowed and/or absorbed anywhere within the mouth or alimentary canal,e.g., buccally, sublingually, or via the stomach, small intestine, orlarge intestine. Typical durations of administration from a singledevice or drug reservoir are greater than 4, 8, 12, or 16 hours per day,up to and including 24 hours per day. Administration can also take placeover multiple days from a single device or drug reservoir, e.g.,administration of a drug for 2 or more days, 4 or more days, or 7 ormore days.

As used herein, “aqueous” refers to formulations of the inventionincluding greater than 10% or 20% (w/w) water and, optionally, acosolvent (e.g., propylene glycol, glycerol or ethanol) or solute (e.g.,a sugar).

By “alkyl saccharide” is meant a sugar ether of a hydrophobic alkylgroup (e.g., typically from 9 to 24 carbon atoms in length). Alkylsaccharides include alkyl glycosides and alkyl glucosides. Alkylglycosides that can be used in the pharmaceutical compositions of theinvention include, without limitation, C₈₋₁₄ alkyl (e.g., octyl-,nonyl-, decyl-, undecyl-, dodecyl-, tridecyl-, or tetradecyl-) ethers ofa or β-D-maltoside, -glucoside or -sucroside, alkyl thiomaltosides, suchas heptyl, octyl, dodecyl-, tridecyl-, and tetradecyl-β-D-thiomaltoside;alkyl thioglucosides, such as heptyl- or octyl 1-thio α- orβ-D-glucopyranoside; alkyl thiosucroses; and alkyl maltotriosides. Forexample, the pharmaceutical composition can include a surfactantselected from octyl maltoside, dodecyl maltoside, tridecyl maltoside,and tetradecyl maltoside. Alkyl glucosides that can be used in thepharmaceutical compositions of the invention include, withoutlimitation, C₈₋₁₄ alkyl (e.g., octyl-, nonyl-, decyl-, undecyl-,dodecyl-, tridecyl-, or tetradecyl-) ethers of glucoside, such asdodecyl glucoside or decyl glucoside.

The term “automatic stop/start,” as used herein, refers to an elementswitching automatically between drug administering mode andnon-administering mode upon actuation by an external stimulus (e.g.,detachment of the device of the invention from an intraoral surface).Automatic stop/start encompasses automatically stopping delivery,automatically starting delivery, or both. For example, the automaticstop/start can be a pressure sensitive switch, a clip, a fluidic channelthat kinks, a clutch (see FIGS. 7E and 7F).

The term “bite-resistant structural supports,” as used herein, refers tostructural elements in the drug delivery device that enable them towithstand a patient's bite with a force of at least 200 Newtons, withoutrupturing and without infusing a bolus of greater than 5% of the drugcontents, when a fresh reservoir is newly inserted into the mouth.

The term “CD” refers to Carbidopa.

As used herein, “co-administered” or “co-infused” refers to two or morepharmaceutically active agents, formulated together or separately, andadministered or infused into the mouth simultaneously or within lessthan 60, 30, 15, or 5 minutes of each other.

The term “COMT” refers to catechol-O-methyl transferase.

As used herein “continuous administration” or “continuous infusion”refers to uninterrupted administration or infusion of a drug in solid orfluid form.

As used herein the term “D₅₀” is defined as the median for a volumedistribution (as opposed to a mass, number, or surface distribution) ofthe particles. The particle size can be measured by conventionalparticle size measuring techniques well known to those skilled in theart. Such techniques include, for example, optical microscopy, electronmicroscopy, sedimentation, field flow fractionation, photon correlationspectroscopy, light scattering (e.g., with a Microtrac UPA 150, MalvernMastersizer), laser diffraction, and centrifugation. D₅₀ values arecommonly derived of particle size distributions of particles suspendedin a non-solvent, the distributions measured by light scattering.

The term “DDC” refers to DOPA decarboxylase.

As used herein, the term “drug particle” refers to solid particlesincluding a drug. The drug particles can be included in thepharmaceutical compositions of the invention. For example, thepharmaceutical composition can contain particulates containing or formedfrom LD, LD salts, CD, or CD salts.

As used herein the term “emulsion” refers to a macroscopicallysubstantially homogeneous system typically including solid drugparticles, water, and a water-immiscible phase (e.g., oil). An emulsionmay remain substantially homogeneous, e.g., it may not substantiallycream or phase separate in 3 months at 25° C. and/or in 1 day at 37° C.The term encompasses oil in water emulsions and water in oil emulsions.

As used herein the term “engineering plastic” is synonymous with theterms “engineered plastic”, “engineered polymer” and “engineeringpolymer”. The term means a polymer differing from the most widely usedpolymers in its superior mechanical properties, or in its superiorresistance to chemicals or its lesser wetting by water or by oils, orits lesser swelling in water or in oils. Exemplary engineering plasticsinclude polyamides such as Nylon 6, Nylon 6-6 and other Nylons;polyesters like polybutylene terephthalate or polyethyleneterephthalate; polycarbonates; polyetheretherketones; polyetherketones;polyimides; polyoxymethylenes such as polyacetals or polyformaldehydes;polyphenylene sulfide; polyphenylene oxide; polysulphone;polytetrafluoroethylene; polyvinylidene difluoride;ultra-high-molecular-weight polyethylene; and strong elastomers such ashighly crosslinked acrylonitrile butadiene styrene, and theirco-polymers.

By “ester saccharide” is meant a sugar ester of a hydrophobic alkylgroup (e.g., typically from 8 to 24 carbon atoms in length). Estersaccharides include ester glycosides and ester glucosides. Esterglycosides that can be used in the pharmaceutical compositions of theinvention include, without limitation, C₈₋₁₄ alkyl (e.g., octyl-,nonyl-, decyl-, undecyl-, dodecyl-, tridecyl-, or tetradecyl-) esters ofa or β-D-maltoside, -glucoside or -sucroside. For example, thepharmaceutical compositions can include a surfactant selected fromsucrose mono-dodecanoate, sucrose mono-tridecanoate, or sucrosemono-tetradecanoate.

As used herein, the term “fastener” refers to an element for attachingthe device of the invention, or its components, to a surface of themouth (e.g., to the teeth). Exemplary methods of attachment arefasteners banded, adhered, cemented or glued to one, two or more teeth;dental appliances; splints; transparent retainers; metal wire Hawleyretainers; partial retainers on one side of the mouth (e.g., attached to3, 4, or 5 teeth); thermo or vacuum-formed Essix retainers typicallyincluding a polypropylene or polyvinylchloride material, typically0.020″ or 0.030″ thick; thermo-formed Zendura retainers includingpolyurethane; bonded (fixed) retainers including a passive wire bondedto the tongue-side of lower or upper teeth; muco-adhesives that adhereto the oral mucosal tissue and slowly erode; and fasteners that conformor are molded to fit a patient's teeth or soft tissue, similar to dentalsplints used to treat bruxism and sleep apnea. Similarly, the drugdelivery devices, drug pumps, drug reservoirs and other devices of theinvention may be directly or indirectly attached to a removable denture,a prosthetic tooth crown, a dental bridge, a moral band, a bracket, amouth guard, or a dental implant.

As used herein the term “fluctuation index” refers to the magnitude ofthe rise and fall of drug level in plasma relative to the average plasmaconcentration, and is defined as [C_(max)−C_(min)]/C_(avg). Thefluctuation index is measured over a specified period of time. The timeperiod can begin, for example, after the drug's plasma concentration:has reached the steady-state concentration; or has reached 90% of thesteady-state concentration; or 30, 60, or 120 minutes after any of thedrug delivery devices of the invention has been inserted into the mouthand begun to deliver drug. The time period can end, for example: at theend of the use period specified in the instructions for use of the drugdelivery device; when the drug reservoir is 90% depleted orsubstantially depleted; or about 4, 8, 16, 24, 72, or 168 hours afterthe start of the time period.

As used herein, the term “fluid” encompasses any drug-including liquid,gel, or non-pourable suspension that can be pumped or extruded. Thefluid can be a Newtonian or a non-Newtonian fluid; it can be an easy todeform solid or a soft paste, which may move as a plug via slip flow. Itcan be, for example, a viscous Newtonian or non-Newtonian suspension.The term encompasses, for example, true solutions, colloidal solutions,emulsions, pastes, suspensions, and dense semi-solid toothpaste-likesuspensions deforming under pressure sufficiently to be extruded intothe mouth. The fluid infused can be aqueous, non-aqueous, single phase,two-phase, three-phase or multiphase. The emulsions can be, for example,oil-in-water or water-in-oil, and can include micelles and/or liposomes.

As used herein, “infused” or “infusion” includes infusion into any partof the body, preferably infusion into the mouth or nasal cavity. It isexemplified by extrusion into the mouth.

The term “LD” refers to levodopa, also known as L-DOPA, or a saltthereof.

As used herein the term “lubricant” means an oil, grease or lamellarsolid that reduces the friction between two parts of a system having amoving component.

The term “MAO-B” refers to monoamine oxidase-B.

As used herein, “mechanical pump” means any drug delivery device whosemotive force is not electricity, magnetism, or gravity. Examples ofmechanical pumps include drug delivery devices wherein the drug isdelivered by the force or pressure of a spring, an elastomer, acompressed gas, or a propellant.

As used herein, “mouth” includes the areas of the oral cavity, includingthose areas of the oral cavity adjacent the lips, cheeks, gums, teeth,tongue, roof of the mouth, hard palate, soft palate, tonsils, uvula, andglands.

The term “non-aqueous” can refer to the liquid carrier in a formulationor to the typically water insoluble liquid component in a formulation.The non-aqueous liquid component typically melts or softens below 37° C.and contains less than 20% (w/w) water (e.g., less than 10%, 5%, 3%, 2%,1.5%, 1%, 0.5%, or less than 0.1% (w/w). Exemplary liquid componentsinclude lipids, edible oils, non-toxic esters of mid-range fatty acids,such as triglyceride esters of mid range fatty acids, butters, andparaffin oils melting or softening below 37° C.

As used herein, the term “operational life” means the time period duringwhich the infused formulation containing the drug (e.g., LD or CD) issuitable for delivery into a patient, under actual delivery conditions.The operational life of the drugs (e.g., LD or CD) delivered by thedevices of the invention can be greater than 12 hours, 24 hours, 48hours, 72 hours, 96 hours (4 days), or 7 days. It typically requiresthat the product is not frozen or refrigerated. The product is typicallyinfused at or near body temperature (about 37° C.) and typically remainssubstantially homogeneous during its infusion.

As used herein, an “oral liquid impermeable reservoir” means a reservoirincluding one or more drugs to be administered into the patient's mouth,wherein, for example, 1, 4, 8, 16, 24, 48 or 72 hours after placing adrug delivery device including a fresh reservoir in a patient's mouthand initiating the administration, less than 5% (e.g., 3% or 1%) byweight of the drug-including pharmaceutical composition in the reservoirincludes an oral liquid. The one or more drugs may be in solid form orin fluid form. Oral liquids include any fluid originating from themouth, including saliva (or its water component) and other fluidscommonly found in the mouth or that are commonly drunk or consumed bythe patient, including diluted oils and alcohols. Exemplary oral liquidimpermeable reservoirs can be made of a metal, or a plastic that canoptionally be elastomeric. Metallic reservoirs can include, for examplealuminum, magnesium, titanium, iron, or alloys of these metals. Whenmade of a plastic it can have a metallic barrier layer; or includeplastics or elastomers that do not substantially swell in water, usedfor example for packaging of food, or for drink-containing bottles, orin a fabric of washable clothing (e.g., polyamides like Nylon orpolyesters like Dacron), or in stoppers or seals of drink containingbottles, or in septums of vials containing solutions of drugs. Examplesinclude perfluoropolymers like PTFE or FPE or fluorinated polyethers,polyolephins like polyethylene and polypropylene; other vinylic polymerslike polystyrene and polyvinylchloride; polyvinylidene chloride,polyacrylates and polymethacrylates, e.g., polymethyl methacrylate andpolymethyl acrylate; and polycarbonates; and polysilicones or theircopolymers. The polymers can have glass transition temperatures greaterthan 37° C. Ingress of oral liquids into openings in the reservoir canbe prevented or minimized by the use of one or more valves, squeegees,baffles, rotating augers, rotating drums, propellants, pneumatic pumps,diaphragm pumps, hydrophobic materials, and/or hydrophobic fluids. Insome embodiments, the invention features multiple doses of solid drugwithin multiple, impermeable reservoirs or compartments. The plastic ofthe reservoir can be fiber reinforced, e.g., with carbon, glass, metalor strong polymer fibers.

The abbreviation “M” means moles per liter. Usage of the term does notimply, as it often does in chemistry, that the drug is dissolved. Asused herein 1 M means that a 1 liter volume contains 1 mole of thecombination of the undissolved (often solid) and/or the dissolved drug.For example, 1 M LD means that there is 197 mg of solid (undissolved)and dissolved LD in one mL.

The term “PD” refers to Parkinson's disease, including patients withscores of 4 and 5 on the Hoehn and Yahr scale.

The term “PEG” refers to polyethylene glycol.

As used herein, the term “pH” refers to the pH measured using a pH meterhaving a glass pH electrode connected to an electronic meter.

As used herein, the term “physically stable” refers to a macroscopicallysubstantially homogenous composition including a suspension of drugparticles, wherein the suspension does not exhibit substantialsedimentation upon (a) storage at about 5° C. under at about 1 G gravityfor a period of at least 3, 6, 12, or 18 months; (b) storage at about25° C. at about 1 G gravity for a period of at least 3, 6, 12, 18, ormore months; or (c) centrifugation at about 5,000 G, 10,000 G, or 16,000G gravity for at least 30 minutes (e.g., for 60 minutes or longer) atabout 25° C. For compositions that include an emulsion includingsuspended drug particles, physically stable compositions also do notexhibit substantial creaming upon (a) storage at about 5° C. underambient conditions for a period of at least 3, 6, 12, or 18 months; (b)storage at 25° C. under ambient conditions for a period of at least 3,6, 12, or 18 months; or (c) centrifugation at about 5,000 G, 10,000 G,or 16,000 G gravity for at least 30 minutes (e.g., 60 minutes or longer)at about 25° C. Physically stable suspensions may also remainmacroscopically substantially homogeneous when stored for about 8, 24,or 48 hours at about 37° C. without agitation, such as shaking,subsequent to the storage or centrifugation described above.

By “polyglycolized glyceride” is meant a polyethylene glycol glyceridemonoester, a polyethylene glycol glyceride diester, a polyethyleneglycol glyceride triester, or a mixture thereof containing a variableamount of free polyethylene glycol, such as a polyethylene glycol-oiltransesterification product. The polyglycolized glyceride can includeeither monodisperse (i.e., single molecular weight) or polydispersepolyethylene glycol moieties of a predetermined size or size range(e.g., PEG2 to PEG 40). Polyethylene glycol glycerides include, forexample: PEG glyceryl caprate, PEG glyceryl caprylate, PEG-20 glyceryllaurate (Tagat® L, Goldschmidt), PEG-30 glyceryl laurate (Tagat® L2,Goldschmidt), PEG-15 glyceryl laurate (Glycerox L series, Croda), PEG-40glyceryl laurate (Glycerox L series, Croda), PEG-20 glyceryl stearate(Capmul® EMG, ABITEC), and Aldo® MS-20 KFG, Lonza), PEG-20 glyceryloleate (Tagat® O, Goldschmidt), and PEG-30 glyceryl oleate (Tagat® 02,Goldschmidt). Caprylocapryl PEG glycerides include, for example,caprylic/capric PEG-8 glyceride (Labrasol®, Gattefosse), caprylic/capricPEG-4 glyceride (Labrafac® Hydro, Gattefosse), and caprylic/capric PEG-6glyceride (SOFTIGEN®767, Huls). Oleoyl PEG glyceride include, forexample oleoyl PEG-6 glyceride, (Labrafil M1944 CS, Gattefosee). LauroylPEG glycerides includes, for example, lauroyl PEG-32 glyceride(Gelucire® ELUCIRE 44/14, Gattefosse). Stearoyl PEG glycerides include,for example stearoyl PEG-32 glyceride (Gelucrire 50/13, Gelucire 53/10,Gattefosse). PEG castor oils include PEG-3 castor oil (Nikkol CO-3,Nikko), PEG-5, 9, and 16 castor oil (ACCONON CA series, ABITEC), PEG-20castor oil, (Emalex C-20, Nihon Emulsion), PEG-23 castor oil (EmulganteEL23), PEG-30 castor oil (Incrocas 30, Croda), PEG-35 castor oil(Incrocas-35, Croda), PEG-38 castor oil (Emulgante EL 65, Condea),PEG-40 castor oil (Emalex C-40, Nihon Emulsion), PEG-50 castor oil(Emalex C-50, Nihon Emulsion), PEG-56 castor oil (Eumulgin® PRT 56,Pulcra SA), PEG-60 castor oil (Nikkol CO-60TX, Nikko), PEG-100 castoroil, PEG-200 castor oil (Eumulgin® PRT 200, Pulcra SA), PEG-5hydrogenated castor oil (Nikkol HCO-5, Nikko), PEG-7 hydrogenated castoroil (Cremophor WO7, BASF), PEG-10 hydrogenated castor oil (NikkolHCO-10, Nikko), PEG-20 hydrogenated castor oil (Nikkol HCO-20, Nikko),PEG-25 hydrogenated castor oil (Simulsol® 1292, Seppic), PEG-30hydrogenated castor oil (Nikkol HCO-30, Nikko), PEG-40 hydrogenatedcastor oil (Cremophor RH 40, BASF), PEG-45 hydrogenated castor oil(Cerex ELS 450, Auschem Spa), PEG-50 hydrogenated castor oil (EmalexHC-50, Nihon Emulsion), PEG-60 hydrogenated castor oil (Nikkol HCO-60,Nikko), PEG-80 hydrogenated castor oil (Nikkol HCO-80, Nikko), andPEG-100 hydrogenated castor oil (Nikkol HCO-100, Nikko). Additionalpolyethylene glycol-oil transesterification products include, forexample, stearoyl PEG glyceride (Gelucire® 50/13, Gattefosse). Thepolyglycolized glycerides useful in the pharmaceutical compositions ofthe invention can include polyethylene glycol glyceride monoesters,diesters, and/or triesters of hexanoic, heptanoic, caprylic, nonanoic,capric, lauric, myristic, palmitic, heptadecanoic, stearic, arachidic,behenic, lignoceric, α-linolenic, stearidonic, eicosapentaenoic,docosahexaenoic, linoleic, γ-linolenic, dihomo-γ-linolenic, arachidonic,oleic, elaidic, eicosenoic, erucic, or nervonic acid, or mixturesthereof. The polyglycol moiety in a polyglycolized glyceride can bepolydisperse; that is, they can have a variety of molecular weights.

By “polysorbate surfactant” is meant an oily liquid derived frompegylated sorbitan esterified with fatty acids. Common brand names forpolysorbate surfactant include Alkest™, Canarcel™ and Tween™.Polysorbate surfactants include, without limitation, polyoxyethylene 20sorbitan monolaurate (TWEEN™ 20), polyoxyethylene (4) sorbitanmonolaurate (TWEEN™ 21), polyoxyethylene 20 sorbitan monopalmitate(TWEEN™ 40), polyoxyethylene 20 sorbitan monostearate (TWEEN™ 60); andpolyoxyethylene 20 sorbitan monooleate (TWEEN™ 80).

The term “pressure-invariant pump,” as used herein, refers to a pumpwhose average rate of drug delivery decreases by less than about 10%(e.g., less than about 7%, 5%, or 3%) at an ambient pressure of about1.013 bar versus its average rate of delivery at an ambient pressure ofabout 0.898 bar and/or increases by less than about 10% (e.g., asdescribed herein) at an ambient pressure of about 0.898 bar versus itsaverage rate of delivery at an ambient pressure of about 1.013 bar.

As used herein, “pump” refers to any mechanism capable of administeringa fluid formulated drug product over a period of 4 or more hours.Examples of pumps include battery-powered pumps (e.g., syringe pumps,piezoelectric, peristaltic pumps, or diaphragm pumps), mechanicaldevices with or without moving parts that are not battery-powered (e.g.,gas-driven pumps, spring-driven pumps, shape memory alloy driven pumps,and elastomeric pumps), and battery operated electroosmotic pumps (withor without moving parts).

The terms “semi-continuous administration” and “frequentadministration,” as used interchangeably herein, refer to anadministration (e.g., infusion) of a drug in solid or fluid form at afrequency of at least once every 120 minutes, and preferably at leastevery 90, 60, 30, 15, or 5 minutes.

As used herein, the term “shelf life” means the shelf life of the drugdelivered by the inventive device (e.g., LD or CD), in its form as aproduct sold for use by consumers, during which period the product issuitable for use by a patient. The shelf life of the drugs (e.g., LD orCD) administered by the devices of the invention can be greater than 3,6, 12, 18, or preferably 24 months. The shelf life may be achieved whenthe product is stored frozen (e.g., at about −18° C.), storedrefrigerated (at 5±3° C., for example at 4±2° C.), or stored at roomtemperature (e.g., at about 25° C.). The drug (e.g., LD or CD) productsold to consumers may be the drug-containing suspension, e.g.,suspension ready for infusion, or it may be its components.

As used herein, “stable” refers to stable formulations of any of thedrugs administered by the devices of the invention. Stable formulationsexhibit physical stability (as defined above) and a reducedsusceptibility to chemical transformation (e.g., oxidation) prior toadministration into a patient. Stable drug formulations have a shelflife at about 5° C. and/or at about 25° C. of equal to or greater than3, 6, 12, 18, or 24 months, and an operational life of greater than orequal to 8 hours, 12 hours, 16 hours, 24 hours, 48 hours, 72 hours, 96hours, or 7 days. In the context of LD and/or CD containingformulations, “stable” refers to formulations which are chemicallystable and physically stable. Chemically stable formulations are thosehaving a shelf life during which less than 20% (e.g., 10%, 5%, 4%, 3%,2% or less than 1%) of the LD and/or CD is chemically transformed (e.g.,oxidized) when stored for a period of 3, 6, 12, 18, or 24 months. Forformulations such as suspensions and drug particle-containing emulsions,the term “stable” also refers to formulations that are physicallystable. In the context of LD and CD, “stable” refers to formulationsthat are “oxidatively stable.” Stable formulations of LD and CD arethose having a shelf life during which less than 10% (e.g., 5%, 4%, 3%,2% or less than 1%) of the LD and CD is oxidized when stored for aperiod of 3, 6, 12, 18, or 24 months. Stable formulations of LD and CDhave an operational life during which less than 10% (e.g., as describedherein) of the LD and CD is oxidized over a period of 8 hours, 12 hours,16 hours, 24 hours, 48 hours, 72 hours, 96 hours, or 7 days. Thechemically stable formulations may contain less than 1.6 μg of hydrazineper mg of LD and CD when stored for a period of 3, 6, 12, 18, or 24months at about 5° C. and/or at about 25° C.

As used herein, “substantially free of oxygen” refers to compositionspackaged in a container for storage or for use wherein the packagedcompositions are largely free of oxygen gas (e.g., less than 10%, orless than 5%, of the gas that is in contact with the composition isoxygen gas) or wherein the partial pressure of the oxygen is less than15 torr, 10 torr, or 5 torr. This can be accomplished, for example, byreplacing a part or all of the ambient air in the container with aninert gas, such as nitrogen, carbon dioxide, argon, or neon, or bypackaging the composition in a container under a vacuum.

The term “suction-induced flow limiter,” as used herein, refers to oneor more elements preventing the delivery of a bolus greater than about5%, 3%, or 1% of the contents of a fresh drug reservoir, when theambient pressure drops by 0.14 bar for a period of one minute. Thesuction-induced flow limiter can include pressurized surfaces that arein fluidic (gas and/or liquid) contact with the ambient atmosphere viaone or more ports or openings in the housing of the drug deliverydevice. Alternatively, the suction-induced flow limiter can be selectedfrom a deformable channel, a deflectable diaphragm, a compliantaccumulator, an inline vacuum-relief valve, and a float valve.

As used herein, the term “suitable for continuous or frequentintermittent intra-oral delivery” refers to drug particle suspensions ofthe invention that are efficacious and safe upon intra-oral delivery.For example, local adverse events in or near the mouth (if any) producedby continuous or frequent intermittent intra-oral administration of thesuspension are tolerable or mild.

As used herein the term “suspension” refers to a mixture including aliquid and particles of at least one solid. The liquid can be aqueous ornon-aqueous or an emulsion. The non-aqueous liquid can be an edible oiland the emulsion can include an edible oil. Suspensions may be, forexample, flowing suspensions or suspensions that are extruded, i.e.,slipping as a plug (e.g., through a flow-controlling orifice, nozzle, ortubing).

The term “suspension flow-enhancement element,” as used herein, refersto one or more elements that substantially prevent pressure-inducedseparation of pumped, viscous suspensions, e.g., formulations withparticular multimodal particle size distributions, packing densities,and flow-enhancing excipients; flaring of the orifice, tube, or flowrestrictor; orifice, tube or flow restrictor inner diameterssubstantially larger than the maximum particle size (e.g., the D₉₀, D₉₅,or D₉₈); and selection of specific combinations of viscosity,orifice/tube inner diameter, particle size, and pressure.

The term “temperature-induced flow limiter,” as used herein, refers toone or more elements preventing the delivery of a bolus greater thanabout 5% of the contents of a fresh drug reservoir, when immersed forfive minutes or for one minute in a stirred physiological salinesolution at about 55° C. The temperature-induced flow limiter caninclude insulation with a material of low thermal conductivity proximatethe drug reservoir and/or the pump. Optionally, the temperature-inducedflow limiter includes an elastomer, a spring, or a gas.

As used herein, the term “treating” refers to administering apharmaceutical composition for prophylactic and/or therapeutic purposes.To “prevent disease” refers to prophylactic treatment of a patient whois not yet ill, but who is susceptible to, or otherwise at risk of, aparticular disease. To “treat disease” or use for “therapeutictreatment” refers to administering treatment to a patient alreadysuffering from a disease to ameliorate the disease and improve thepatient's condition. The term “treating” also includes treating apatient to delay progression of a disease or its symptoms. Thus, in theclaims and embodiments, treating is the administration to a patienteither for therapeutic or prophylactic purposes.

As used herein “viscosity” means dynamic viscosity also known as shearviscosity.

Other features and advantages of the invention will be apparent from thefollowing Detailed Description, the drawings, and the claims.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1A depicts a drug delivery device that is removably attached to atooth using a fastener 1. The pump 2 and drug reservoir 3 are containedwithin a housing 4 and are disposable. FIG. 1B depicts an embodiment inwhich a portion 4 of the drug delivery device is reusable, and aremovable pump 2 and drug reservoir 3 can be disposable. FIG. 1C depictsan embodiment in which a pump 2 and a drug reservoir 3 form a singlecomponent.

FIG. 2A depicts an embodiment of the drug delivery device in which thepump 2 and/or drug reservoir 3 is fastened to either the upper or lowerteeth using a transparent retainer 6. One, two or more pumps and/or oneor more drug reservoirs are secured on the buccal side of thetransparent retainer 6. One, two, or more drug pumps and/or drugreservoirs may be secured unilaterally, on either the right or leftsides, positioned in the buccal vestibule or, alternatively, on thelingual side of the teeth. FIG. 2B is a close up showing the pump 2 anddrug reservoir 3 attached to the transparent retainer 6 and dispensingdrug to the lingual side of the mouth through a tube 5.

FIG. 3 depicts a drug delivery device in which the pump 2 and drugreservoir 3 are configured to be positioned both on the lingual side ofthe teeth and in the bucal vestibule. The drug reservoir is fastened onthe lingual side of the teeth, while a drug pump and an optional gaspump 11 are positioned on the buccal side of the teeth.

FIG. 4A depicts a fastener in the form of a transparent retainer 6,including two bilateral housings 4 (shown empty) on the buccal side ofthe teeth into which drug pumps and/or drug reservoirs may be inserted.FIG. 4B depicts a fastener in the form of an invisible retainer 6,including two bilateral housings 4 (shown filled) on the lingual side ofthe teeth into which drug pumps and/or drug reservoirs 3 have beeninserted.

FIGS. 5A and 5B illustrate a drug delivery device including apressurized, drug-filled polymer such as an elastomer. The elastomerprovides pressure that delivers the drug at a constant rate through anarrow internal diameter tubing, with the rate determined by theproperties of the elastomer and the inner diameter of the narrow boretubing. FIG. 5A is a representation of an empty elastomeric drugdelivery device, while FIG. 5B represents a fresh, pressurized,drug-filled elastomeric drug delivery device.

FIGS. 5C and 5D illustrate an elastomeric band-driven pump employing arubber band 10 to pull a piston 13 to apply pressure to the drugreservoir 3.

FIG. 6 illustrates the use of a motor to rotate two columnar or conicalshaped drums 29 that are attached to the oral liquid impermeable drugreservoir 3.

FIGS. 7A, 7B, 7C, and 7D illustrate spring-driven pumps in which aconstant force spring is used to compress the drug reservoir 3.

FIGS. 7E and 7F illustrate a spring loaded clutch mechanism 85 useful inthe devices of the invention. The clutch mechanism engages the piston 39to inhibit the force transmission to the drug reservoir 3 prior to use.When the device is removed from the mouth, the protrusion 84 isdisengaged, stopping the release of drug from the drug reservoir 3.

FIG. 8 illustrates a constant force compression-spring driven pumpdelivering a drug suspension.

FIG. 9 illustrates two coaxial compression springs wherein, uponcompression, a first spring with a first diameter is wholly or partiallynested within a second spring with a second, larger diameter.

FIG. 10 illustrates a disk 54 which contains compartments filled withdrug suspension 55 that are injected by an air pressure bolus at apre-determined rate through an orifice 56 that is fixed in place withrespect to the rotating disk. The rotation of the disk, via a springmechanism 37, exposes a single compartment and the bolus of air deliversthe drug from that compartment to the mouth.

FIGS. 11A, 11B, and 11C illustrate a drug delivery device wherein afirst elastomeric drug reservoir 3 is compressed by a second elastomericreservoir or balloon 7 containing gas or propellant (partially or mostlyliquified). In FIG. 11A, the drug delivery device includes a housingcontaining a first, full elastomeric drug reservoir 3; a secondelastomeric reservoir 7 substantially empty of gas and optionallycontaining liquid propellant; and an optional gas pump 11 andelectronics. In one embodiment air is pumped by the electronic (e.g.,piezoelectric) pump 11 into the second elastomeric reservoir 7. Thepressure from the second elastomeric reservoir 7 compresses the firstelastomeric drug reservoir 3 containing the drug, forcing the drug outof the reservoir through a flow restrictor 58 at a constant rate. FIG.11B illustrates the system with a first, half-full drug reservoir 3 anda second, elastomeric reservoir 7 half-filled with pressurized air orpropellant. FIG. 11C illustrates the system when the drug reservoir 3 isclose to empty. In another embodiment, saliva can be pumped by theelectronic pump 11 into the second elastomeric reservoir 7.

FIG. 12 shows a schematic of a typical two stage gas pressure regulator.

FIGS. 13A and 13B illustrate a drug delivery device including anexpandable plastic (elastomeric or non-elastomeric) compartment 61containing propellant within a rigid drug reservoir 3. The propellantwithin the expandable plastic compartment has a vapor pressure thatpressurizes the drug compartment at a specific pressure when exposed tobody temperature, and pushes the drug through a narrow bore tubing. FIG.13A shows the compressed expandable plastic compartment 61 containingpropellant within the full drug reservoir 3. FIG. 13B shows the nearlyempty drug reservoir 3 and the expanded expandable plastic compartment61 containing propellant.

FIGS. 14A, 14B, 14C, and 14D illustrate a propellant-driven drugdelivery device for the delivery of suspensions.

FIGS. 15A, 15B, 16A, 16B, 16C, 16D, 17A, 17B, and 17C illustratemechanisms which make the drug delivery rate of drug delivery devicesinsensitive to ambient pressure changes in the mouth.

FIGS. 18A and 18B are graphs of the temperature in two locations in themouth after ingestion of a hot beverage.

FIGS. 19A and 19B are graphs of the temperature in two locations in themouth after ingestion of a cold beverage.

FIG. 20 illustrates an embodiment of efficient drug packing using drugparticles with a tri-modal size distribution.

FIGS. 21A and 21B are micrographs depicting LD particles formed by jetmilling to reduce the average size of the particles (excluding fines)(see Example 6).

FIG. 22 illustrates a drug reservoir 4 with a tapered flow path leadingto the orifice 75.

FIGS. 23A, 23B, and 23C illustrate an embodiment of a propellant-drivenpump including a propellant-containing chamber and a pharmaceuticalcomposition-containing chamber separated by a flexible and/or deformablediaphragm.

FIG. 24 shows a port 102 in a pump housing 101 forming a wall of achamber 89 containing a pharmaceutical composition with an elastomericgrommet 94 inserted into the port. A filling nozzle 95 may be insertedthrough the grommet to fill the drug-containing chamber 89 with thepharmaceutical composition.

FIG. 25 illustrates a port 102 in a pump housing 101 forming a wall of achamber 89 containing a pharmaceutical composition with an elastomericgrommet 94 inserted into the port. After filling the drug-containingchamber through the port, the port may then be removed and replaced withthe delivery nozzle 96.

FIG. 26 illustrates a propellant-driven pump including grooves in thesurfaces of the chamber including the pharmaceutical composition.

FIG. 27 illustrates titantium coupons that were resistance welded,(i.e., brazed) to silver diaphragms by applying an electrical currentpulse or pulses.

FIG. 28 is a schematic drawing of a stamp die block, cover plate, andpunch designed to form flexible and/or deformable metal diaphragms.

FIG. 29 shows a tool used to make flexible and/or deformable metaldiaphragms.

FIG. 30 shows a flexible and/or deformable metal diaphragm.

FIG. 31 shows schematics for a titanium test housing including fittingsthat allowed for testing for hermeticity. The test housing is welded toa silver diaphragm.

FIG. 32 shows a test housing for a propellant-driven pump.

FIG. 33 is a graph showing the time dependence of the mass of thedelivered pharmaceutical composition for the device of FIG. 32. Thegraph shows that the slope, i.e., the rate of delivery, was not constantover the 100 min extrusion period.

FIG. 34 is a graph showing the time dependence of rate of delivery,i.e., rate of extrusion, of the pharmaceutical composition for thedevice of FIG. 33. The graph shows that the rate was not constant overthe 100 min extrusion period.

FIG. 35 shows incomplete emptying of the pharmaceutical composition fromthe device of FIG. 32.

FIG. 36 shows flow-enhancing grooves in the interior housing wall of thedrug-containing chamber for a propellant-driven pump.

FIG. 37 is a graph showing the time dependence of the mass of thedelivered, i.e., extruded, pharmaceutical composition for the device ofFIG. 36.

FIG. 38 is a graph of showing the time dependence of the rate ofdelivery, i.e., extrusion, of the pharmaceutical composition for thedevice of FIG. 36.

FIG. 39 shows the housing of a propellant-driven pump including twotubes that include flow channels for the drug-including pharmaceuticalcomposition.

FIG. 40 is a graph showing that the time dependence of the mass of thepharmaceutical composition delivered for the device of FIG. 39 islinear, i.e., that the rate of delivery of the drug-including fluid isconstant.

FIG. 41 is a graph showing the time dependence of the rate of delivery,i.e., the rate of extrusion of the pharmaceutical composition for thedevice of FIG. 39. The rate of delivery, i.e., extrusion, is aboutconstant.

FIG. 42 is a bar chart showing the fluctuation index for each two hourinterval during on Day 2 and on Day 3 during the clinical trialdescribed of Example 53.

FIG. 43 is a bar chart showing the OFF time of each patient on Day 2 andon Day 4 during the clinical trial described of Example 53.

FIG. 44 illustrates the drug delivery device configured to be removablyinserted in a patient's mouth and for continuous or semi-continuousintraoral administration a drug.

DETAILED DESCRIPTION

The devices, compositions, and methods of the invention are useful forcontinuous or semi-continuous oral delivery of medicaments.

While syringes, drug reservoirs and pumps outside the mouth can be largebecause space is typically available, space in the mouth for a drugdelivery device is limited and is particularly limited when a drugdelivery device is so small that it does not interfere with speaking,swallowing, drinking, or eating. Consequently, the delivered drug, itsreservoir and its delivery device must occupy a small volume. In theexemplary management of Parkinson's disease the concentration of theorally infused LD and/or CD including fluid of the invention can betypically greater than 1 M, such as greater than 1.5 M, 2 M, 2.5 M, 3 M,3.5 M, 4 M or 4.5 M. These are substantially higher concentrations thanthe 0.1 M LD concentration of the Duodopa (also known as Duopa™) gelsthat are commercially available for jejunal, gastric or nasogastricinfusions. The concentrated drug suspension can be viscous, for exampleits dynamic viscosity at 37° C. can be much greater than 100 cP, such asgreater than 10,000 cP, 100,000 cP, or 1,000,000 cP. The suspension canhave, for example, viscosity equal to or greater than that oftoothpaste, the viscosity being greater than about 20,000 cP, forexample greater than 50,000 cP, such as greater than 500,000 cP. Theearlier practice of infusion of viscous fluids through long tubings,typically longer than 50 cm, such as those used for nasogastric, gastricor jejunal infusions, required that their internal diameter be largeand/or that the pumping pressure be high. Furthermore, when the earliersuspensions were infused through the longer tubings, the likelihood ofblockage of the flow because of clustering of the suspended LD particlesincreased and translucent, very fine particle colloids were used toreduce blockage. In contrast, the herein disclosed orally infused, moremuch concentrated suspensions of the invention are typically opaquebecause they can contain large solid particles scatteringvisible-wavelength light. The much more concentrated and much moreviscous orally infused suspensions can be rich in particle sizes greaterthan 1 μm, 5 μm, 10 μm, or even 50 μm. The suspensions can be orallyinfused, for example, using orifices in reservoirs that are narrowerthan 2 mm or 1 mm, and/or through optionally plastic tubings or nozzlesthat can be shorter than 5 cm, e.g., shorter than 4 cm, 3 cm, 2 cm or 1cm.

The invention addresses the problem of formulating a pharmaceuticalsuspension that is sufficiently concentrated to be useful for oralinfusion as described above and that is sufficiently physically andchemically stable for long-term storage at room temperature and forinfusion over a prolonged period of time. Thus, the invention features apharmaceutical composition suitable for continuous or frequentintermittent intra-oral delivery. The composition can be a suspension ofsolid drug particles in a carrier that is physically stable at about 25°C. and/or at a physiological temperature, such as 37° C. The suspensioncan contain from about 35% (w/w) to about 70% (w/w) of the drug, thisweight percentage including the solid drug particles and the drugdissolved in the carrier. The carrier can include a continuoushydrophilic phase, e.g., it can be an oil-in-water emulsion. It cancontain more oil than water by weight, even when the continuous phase ishydrophilic or when it is an oil-in-water system. Alternatively, it caninclude a continuous hydrophobic (i.e., water-immiscible) phaseincluding an oil or a water-in-oil emulsion.

Physical stability of the solid drug particle containing suspension canbe enhanced by the combined presence of an oil, water and a surfactant,each in an amount sufficient to inhibit or retard sedimentation and/orphase separation.

The invention also features levodopa and carbidopa formulations that arechemically stable, with chemical degradation products of the levodopaand carbidopa (e.g., oxidation product and hydrolysis products) of lessthan 5%, 2%, or 1% of the starting amount of the drugs. In particular,the invention features CD and LD/CD formulations with low hydrazineconcentrations, even after prolonged storage or exposure to elevatedtemperatures under air.

Administration in the Mouth

The drugs may be administered intraorally (i.e., onto or near anyintraoral surface, e.g., the lips, cheeks, gums, teeth, tongue, roof ofthe mouth, hard palate, soft palate, tonsils, uvula, and glands). Thedrugs administered intraorally are typically swallowed by the patient,together with the patient's saliva. The drugs can be diluted by thepatient's saliva and can optionally be partly or fully dissolved in thesaliva. The drugs can be absorbed in the patient's gastrointestinaltract, e.g., in the small intestines or large intestines. In some cases,absorption of drugs delivered by the drug delivery devices of theinvention may take place partially or even primarily through the mucousmembranes in the mouth, e.g., buccal or sublingual absorption.

Medications and Diseases

The devices and methods of the invention are suitable for theadministration of a variety of drugs that have a short half-life and/ora narrow therapeutic range. Complementary drugs may be co-administeredor co-infused with these drugs. Such complementary drugs may improve thepharmacokinetics, improve the efficacy, and/or reduce the side effectsof the primary drugs.

Exemplary diseases/medical conditions that may be treated with thedevices and methods of the invention, and corresponding drugs andexemplary ranges of daily doses and of average administration rates, arelisted below:

-   -   Parkinson's disease: levodopa, levodopa prodrugs, and dopamine        agonists (such as Pramipexole (0.1-10 mg per day, 0.004-0.42        mg/hr), Bromocriptine, Ropinirole (0.25-10 mg per day, 0.01-0.42        mg/hr), Lisuride, Rotigotine). Examples of complementary drugs        for Parkinson's disease, which may optionally be co-infused, are        DDC inhibitors (such as carbidopa and benserazide (50-600 mg per        day, 2.1-25 mg/hr)), COMT inhibitors (such as entacapone,        tolcapone and opicapone), MAO-B inhibitors (such as Rasagiline        and Selegiline), adenosine A2 receptor antagonists (such as        Istradefylline), and gastroparesis drugs (such as Domperidone,        Nizatidine, Relamorelin, Monapride and Cisapride).    -   Allergies: antigens or allergens (e.g., pollen, a part of a        mite, or a component of the feline or canine skin, or an extract        or a conversion product thereof)    -   Anesthesia: bupivacaine, lidocaine.    -   Anxiety: oxcarbazepine (300-3,000 mg per day, 12.5-125 mg/hr),        prazosin (0.2-5 mg per day, 0.01-0.21 mg/hr).    -   Arrhythmia: quinidine (300-2,000 mg per day, 12.5-83 mg/hr)    -   Bacterial infections: beta-lactam antibiotics (e.g.,        cephalosporins).    -   Cancer: capecitabine (1,000-10,000 mg per day, 42-417 mg/hr) and        other 5-fluorouracil prodrugs.    -   Dementia: Rivastigmine.    -   Diabetes: oral insulins    -   Diabetic nephropathy: angiotensin receptor blockers.    -   Disordered sleep: Zaleplon (3-20 mg per day, 0.38-0.83 mg/hr for        8 hours at night), gamma hydroxy butyrate (10-200 mg per day,        1.3-25 mg/hr for 8 hours at night), Zolpidem (3-20 mg per day        0.38-0.83 mg/hr for 8 hours at night), triazolam.    -   Epilepsy and seizures: Oxcarbazepine (300-3,000 mg per day,        12.5-125 mg/hr), topiramate (200-500 mg per day, 8.3-20.8        mg/hr), lamotrigine (100-700 mg per day, 4.2-29.2 mg/hr),        gabapentin (600-3,600 mg per day, 25-150 mg/hr), carbamazepine        (400-1,600 mg per day, 16.7-66.7 mg/hr), valproic acid        (500-5,000 mg per day, 20.1-208 mg/hr), levetiracetam        (1,000-3,000 mg per day, 41.7-125 mg/hr), pregabalin (150-600 mg        per day, 6.25-25 mg/hr).    -   Heart failure: ACE inhibitors, angiotensin receptor blockers.    -   Hypertension: Prazosin (0.2-5 mg per day, 0.01-0.21 mg/hr), ACE        inhibitors, angiotensin receptor blockers.    -   Orthostatic hypotension: droxidopa, fludrocortisone, midodrine.    -   Mood disorders: Oxcarbazepine (300-3,000 mg per day, 12.5-125        mg/hr), lithium.    -   Mucositis: pilocarpine, topical anesthetics or analgesics (e.g.,        lidocaine), mucosal coating agents (e.g., benzydamine HCl), and        sialagogues.    -   Organ transplantation: Cyclosporine (150-1,500 mg per day,        6.3-62.5 mg/hr), Tacrolimus (3-25 mg per day, 0.13-1.04 mg/hr).    -   Pain: Fentanyl (0.05-2.0 mg per day, 0.002-0.083 mg/hr),        Dilaudid (2-50 mg per day, 0.83-2.1 mg/hr).    -   Post-traumatic stress disorder: Prazosin (0.25-5 mg per day,        0.01-0.21 mg/hr).    -   Spasticity: Baclofen.    -   Hyperammonaemia associated with N-acetylglutamate synthase        deficiency, isovaleric acidaemia, methymalonic acidaemia,        propionic acidaemia: carglumic acid.    -   Lambert-Eaton disease: Amifampridine (15-60 mg per day,        0.625-2.5 mg/hour).    -   Myasthenia gravis: pyridostigmine (60-1,500 mg per day, 2.5-62.5        mg/hour. A typical dose is about 600 mg per day or about 25        mg/hour.)

Exemplary diseases/medical conditions that may be treated with thedevices and methods of the invention, and corresponding drugs andexemplary ranges of daily doses and of average administration ratesinclude those that are listed below in Tables A-C.

TABLE A Delivery Daily Daily Dose Range (mg) Drug Indication RouteFormulation Hours Low High Typical Baclofen Multiple sclerosis, GI B, C16 30 100 50 cerebral palsy, spastic conditions Tizanidine Multiplesclerosis, GI, C, F 16 12 36 18 cerebral palsy, spastic Buccalconditions Dantrolene Multiple sclerosis, GI A 16 25 400 100 cerebralpalsy, spastic conditions DroxiDOPA Neurogenic orthostatic GI A 16 3001800 1,000 hypotension Midodrine Neurogenic orthostatic GI B, C 16 25 3530 hypotension Penicillamine Wilson's disease GI A 16 250 2000 500Penicillamine Cystinuria GI A 24 2000 4000 3,000 PenicillamineRefractory rheumatoid GI A 24 250 750 500 arthritis Zinc acetateWilson's disease GI A, D 24 100 200 150 Zinc Wilson's disease GI A, D 2430 80 50 compounds water or stomach acid soluble, dose representing theZn²⁺ content only Magnesium Parkinson's disease; GI A, D 24 500 50003,000 compounds, Alzheimer disease; water or cognitive diseases; stomachacid learning disabilities soluble, dose representing the Mg²⁺ contentonly L-DOPA Parkinson's disease GI A 16 300 3000 1,200 PyridostigmineMyasthenia gravis GI A 16 60 1500 600 Neostigmine Myasthenia gravisBuccal B 16 50 70 60 Miglustat Type-1 Gaucher GI A 24 200 400 300disease, Type C Niemann-Pick disease Cromoglicic Eosinophilic GI A 24 401000 800 acid (cromolyn) gastroenteritis, chronic mastocytosis,ulcerative colitis Metoclopramide Gastroparesis, GI B, C 24 40 30nausea, gastro- oesophageal reflux, gastroenteritis, hyperemesisgravidarum Trientine Wilson's disease GI A 16 1200 2400 1,800Temozolomide Glioblastoma GI A 24 300 400 350 multiformae, anaplasticastrocytoma Captopril Primary hypertension, GI B, C 16 40 60 50 coronaryheart disease, congestive heart failure, angina Acarbose Type 2 diabetesGI A 24 250 350 300 Iloprost PH Buccal F 16 0.02 0.1 0.048 Beraprost PHBuccal F 16 0.2 0.5 0.36 Treprostinil PH GI B,C 16 4 20 12 CiclesonideCOPD, PH Buccal F 16 0.1 0.5 0.24 Flunisolide COPD, PH Buccal F 16 0.52.5 1.2 Budesonide COPD, PH Buccal F 16 0.6 3 1.5 Beclomethason COPD, PHBuccal F 16 0.6 3 1.5 Bosentan COPD, PH GI A 16 100 500 250 MometasoneCOPD, PH Buccal F 16 0.2 1 0.48 Vilanterol COPD Buccal F 24 0.1 0.5 0.24Bitolterol COPD; Asthma GI C 24 2 10 4.8 Levosalbutamol COPD; AsthmaBuccal F 24 0.5 5 2.4 sulfate Salbutamol COPD; Asthma Buccal F 24 0.5 52.4 Salmeterol COPD; Asthma Buccal F 24 0.05 0.25 0.1 GlycopyrroniumCOPD GI F 24 0.02 0.1 0.048 bromide Ipatropium COPD GI F 24 0.3 1.5 0.72bromide Aclidinium COPD GI F 24 0.3 1.5 0.72 bromide Carbocisteine COPDGI A 24 1 3 1500 Erdosteine COPD GI A 24 0.3 1 600 Ambroxol COPD GI A 240.08 0.24 120 Acetylcysteine COPD GI A 24 0.5 1.5 840 ErythromycinGastroparesis GI A 24 50 500 250 Erythromycin Bacterial infection GI A24 500 1500 1000 control in COPD Clarithromycin Bacterial infection GI A24 300 900 500 control in COPD Hexoprenaline Asthma Buccal F 24 0.5 2.51.2 sulfate Pirbuterol Asthma Buccal F 24 0.5 2.5 1.2 Fenoterol AsthmaBuccal F 24 2 10 4.8 Terbutaline Asthma Buccal F 24 1.6 8 4Metaproterenol Asthma Buccal F 24 2 10 4.8 Trimebutine IBS GI A 24 2001000 630 Mebeverine IBS GI A 24 100 500 300 Dicycloverine IBS GI A 24 40200 80 Flavoxate Overactive bladder; GI A 24 200 1000 720 Oxybutininurinary urge GI B, C 24 20 100 14.4 Tolterodine incontinence GI F 24 525 3.6 tartarate Darifenacin GI C 24 10 50 7.2 Curcumin Cancer, e.g.colon, GI A 24 2000 5000 4000 breast, ovarian Curcumin Cancer, e.g.colon, analogs EF24, breast, ovarian GI A 24 2000 5000 4000 EF31, UBS109or FLLL12

TABLE B Exemplary Concentrations Dose Rate (mg/hr) (mg/mL) Drug Low HighTypical Low Middle High Baclofen 1.875 6.25 3.125 20 85 150 Tizanidine0.75 2.25 1.125 10 30 50 Dantrolene 1.563 25 6.25 600 725 850 DroxiDOPA18.75 112.5 62.5 600 725 850 Midodrine 1.563 2.188 1.875 20 85 150Penicillamine 15.625 125 31.25 600 725 850 Penicillamine 83.333 166.667125 600 725 850 Penicillamine 10.417 31.25 20.833 600 725 850 Zincacetate 4.167 8.333 6.25 100 300 500 Zinc compounds water 1.25 3.3332.083 30 90 150 or stomach acid soluble, dose representing the Zn²⁺content only Magnesium compounds, 20.833 208.333 125 200 400 600 wateror stomach acid soluble, dose representing the Mg²⁺ content only L-DOPA18.75 187.5 75 600 725 850 Pyridostigmine 3.75 93.75 37.5 600 725 850Neostigmine 3.125 4.375 3.75 20 85 150 Miglustat 8.333 16.667 12.5 600725 850 Cromoglicic acid 1.667 41.667 33.333 600 725 850 (cromolyn)Metoclopramide 0 1.667 1.25 20 85 150 Trientine 75 150 112.5 600 725 850Temozolomide 12.5 16.667 14.583 600 725 850 Captopril 2.5 3.75 3.125 2085 150 Acarbose 10.417 14.583 12.5 600 725 850 Iloprost 0.001 0.0060.003 0.1 0.3 0.5 Beraprost 0.013 0.031 0.023 0.5 1.75 3 Treprostinil0.25 1.25 0.75 20 60 100 Ciclesonide 0.006 0.031 0.015 0.4 1.2 2Flunisolide 0.031 0.156 0.075 2 6 10 Budesonide 0.038 0.188 0.094 3 9 15Beclomethasone 0.038 0.188 0.094 3 9 15 Bosentan 6.25 31.25 15.625 500675 850 Mometasone 0.013 0.063 0.03 0.8 2.4 4 Vilanterol 0.004 0.0210.01 0.5 1.5 2.5 Bitolterol 0.083 0.417 0.2 10 30 50 Levosalbutamolsulfate 0.021 0.208 0.1 2.5 13.75 25 Salbutamol 0.021 0.208 0.1 2.513.75 25 Salmeterol 0.002 0.01 0.004 0.1 1.3 2.5 Glycopyrronium 0.0010.004 0.002 0.1 0.3 0.5 bromide Ipatropium bromide 0.013 0.063 0.03 1 35 Aclidinium bromide 0.013 0.063 0.03 1 3 5 Carbocisteine 0.042 0.12562.5 600 725 850 Erdosteine 0.013 0.042 25 600 725 850 Ambroxol 0.0030.01 5 500 650 800 Acetylcysteine 0.021 0.063 35 600 725 850Erythromycin 2.083 20.833 10.417 400 600 800 Erythromycin 20.833 62.541.667 700 775 850 Clarithromycin 12.5 37.5 20.833 600 700 800Hexoprenaline sulfate 0.021 0.104 0.05 2 6 10 Pirbuterol 0.021 0.1040.05 2 6 10 Fenoterol 0.083 0.417 0.2 8 24 40 Terbutaline 0.067 0.3330.167 4 12 20 Metaproterenol 0.083 0.417 0.2 8 24 40 Trimebutine 8.33341.667 26.25 600 725 850 Mebeverine 4.167 20.833 12.5 600 725 850Dicycloverine 1.667 8.333 3.333 500 650 800 Flavoxate 8.333 41.667 30600 725 850 Oxybutinin 0.833 4.167 0.6 40 95 150 Tolterodine tartarate0.208 1.042 0.15 10 20 30 Darifenacin 0.417 2.083 0.3 20 35 50 Curcumin83.333 208.333 166.667 600 725 850 Curcumin analogs EF24, 83.333 208.333166.667 600 725 850 EF31, UBS109 or FLLL12

TABLE C Exemplary Delivery Exemplary Daily Rates (μL/hr) Volume (mL)Drug Low Middle High Low High Baclofen 12.5 36.8 312.5 0.3 0.7Tizanidine 15 37.5 225 0.4 0.7 Dantrolene 1.8 8.6 41.7 0.04 0.7DroxiDOPA 22.1 86.2 187.5 0.3 2.5 Midodrine 10.4 22.1 109.4 0.2 0.7Penicillamine 18.4 43.1 208.3 0.3 3 Penicillamine 98 172.4 277.8 2.5 4Penicillamine 12.3 28.7 52.1 0.3 0.9 Zinc acetate 8.3 20.8 83.3 0.2 0.8Zinc compounds 8.3 23.1 111.1 0.2 0.8 water or stomach acid soluble,dose representing the Zn²⁺ content only Magnesium 34.7 312.5 1,041.70 18 compounds, water or stomach acid soluble, dose representing the Mg²⁺content only L-DOPA 22.1 103.4 312.5 0.4 4 Pyridostigmine 4.4 51.7 156.30.5 2 Neostigmine 20.8 44.1 218.8 0.3 0.5 Miglustat 9.8 17.2 27.8 0.250.8 Cromoglicic acid 2 46 69.4 0.5 1.5 (cromolyn) Metoclopramide 0 14.783.3 0.3 0.7 Trientine 88.2 155.2 250 1.5 3 Temozolomide 14.7 20.1 27.80.4 0.6 Captopril 16.7 36.8 187.5 0.3 0.7 Acarbose 12.3 17.2 24.3 0.30.5 Iloprost 2.5 10 62.5 0.04 0.2 Beraprost 4.2 12.9 62.5 0.07 0.7Treprostinil 2.5 12.5 62.5 0.1 0.5 Ciclesonide 3.1 12.5 78.1 0.1 0.5Flunisolide 3.1 12.5 78.1 0.1 0.5 Budesonide 2.5 10.4 62.5 0.1 0.5Beclomethasone 2.5 10.4 62.5 0.1 0.5 Bosentan 7.4 23.1 62.5 0.2 0.7Mometasone 3.1 12.5 78.1 0.1 0.5 Vilanterol 1.7 6.7 41.7 0.1 0.5Bitolterol 1.7 6.7 41.7 0.1 0.5 Levosalbutamol 0.8 7.3 83.3 0.1 0.5Salbutamol 0.8 7.3 83.3 0.1 0.5 Salmeterol 0.8 3.2 104.2 0.1 0.5Glycopyrronium 1.7 6.7 41.7 0.1 0.5 bromide Ipatropium 2.5 10 62.5 0.10.5 bromide Aclidinium 2.5 10 62.5 0.1 0.5 bromide Carbocisteine 0 86.20.2 1 3 Erdosteine 0 34.5 0.1 0.6 1.5 Ambroxol 0 7.7 0 0.1 0.3Acetylcysteine 0 48.3 0.1 0.5 1.5 Erythromycin 2.6 17.4 52.1 0.1 0.8Erythromycin 24.5 53.8 89.3 0.6 2 Clarithromycin 15.6 29.8 62.5 0.4 1Hexoprenaline 2.1 8.3 52.1 0.1 0.5 sulfate Pirbuterol 2.1 8.3 52.1 0.10.5 Fenoterol 2.1 8.3 52.1 0.1 0.5 Terbutaline 3.3 13.9 83.3 0.1 0.5Metaproterenol 2.1 8.3 52.1 0.1 0.5 Trimebutine 9.8 36.2 69.4 0.3 1Mebeverine 4.9 17.2 34.7 0.2 0.8 Dicycloverine 2.1 5.1 16.7 0.08 0.3Flavoxate 9.8 41.4 69.4 0.6 1.2 Oxybutinin 5.6 6.3 104.2 0.2 0.4Tolterodine 6.9 7.5 104.2 0.2 0.4 tartarate Darifenacin 8.3 8.6 104.20.2 0.4 Curcumin 98 229.9 347.2 3 7 Curcumin 98 229.9 347.2 3 7 analogsEF24, EF31, UBS109 or FLLL12

Abbreviations for Tables A-C:

PH: pulmonary hypertension, including pulmonary arterial hypertension

IBS: irritable bowel syndrome

COPD: chronic occlusive pulmonary disease

The drugs and methods of the invention may be used for treating dentaland maxillofacial conditions, such as xerostomia, dental caries, localinfections (e.g., fluconazole, diflucan, nystatin, or clotrimazole forthrush) in the mouth or throat, and local pain in the mouth or throat(e.g., lidocaine).

Dry mouth (xerostomia) and hyposalivation are more prevalent in olderpatients and are a common side effect of medications, includingmedications for the treatment of PD. Patients with PD also commonlyexperience difficulty swallowing (dysphagia), which often results indrooling (sialorrhea). Drugs for the treatment of xerostomia,hyposalivation, dysphagia and/or sialorrhea may be delivered using thedevices and methods of the invention. Examples of drugs for xerostomiaand hyposalivation are saliva stimulants such as organic acids (e.g.,citric acid, ascorbic acid, malic acid) or their acidic salts andparasympathomimetic drugs (e.g., choline esters such as pilocarpinehydrochloride, and cholinesterase inhibitors). Examples of drugs fordysphagia are Scopolamine, Tropicamide, Glyccopyrolate, and BotulinumToxin. Examples of drugs for excess salivation are anticholinergics suchas glycopyrrolate. In a preferred embodiment, drugs for the treatment ofxerostomia, hyposalivation, and/or dysphagia are co-administered withthe LD or CD, using the drug delivery devices and methods of theinvention. In another preferred embodiment, intra-oral administration ofan anti-Parkinson's medication itself stimulates increased salivationand/or more frequent or improved swallowing.

Gastroparesis, or delayed gastric emptying, is common in people with PD,especially in patients with scores of 4 and 5 on the Hoehn and Yahrscale. Drugs for the treatment of gastroparesis may be delivered usingthe devices and methods of the invention. In one embodiment, drugs forthe treatment of gastroparesis are co-administered with the LD or CD,using the drug delivery devices and methods of the invention. In anotherembodiment, drugs for the treatment of gastroparesis are administeredusing other methods of drug delivery known in the art (i.e., they arenot administered via continuous or frequent intra-oral delivery) whileLD or CD are infused intra-orally. Examples of drugs for the treatmentof gastroparesis are Metoclopramide, Cisapride, Erythromycin,Domperidone, Sildenafil Citrate, Mirtazapine, Nizatidine, Acotiamide,Ghrelin, Levosulpiride, Tegaserod, Buspirone, Clonidine, Relamorelin,Serotonin 5-HT4 agonists and dopamine D2 or D3 antagonists.

Methylation of LD, whereby 3-methoxy-levodopa (3-OMD) is produced, isone of the major metabolic paths of LD. It increases the amount of LDrequired by Parkinson's disease patients and because the conversionshortens the half-life of plasma LD, it also increases the frequency atwhich LD or LD/CD or CD need to be administered in order to manage thesymptoms of Parkinson's disease. The conversion of LD to 3-OMD iscatalyzed by the enzyme catechol-O-methyl transferase, COMT.Administration of a COMT inhibitor can reduce the required dosage of LDor LD/CD, or in earlier stages of PD, even provide for managing thedisease without LD or LD/CD. The two most frequently used COMTinhibitors, entacapone and tolcapone are, however short-lived.

Entacapone does not cross the blood-brain barrier and can be less toxicthan Tolcapone, which crosses the barrier. The plasma half-life ofEntacapone is, however, merely 0.4-0.7 hours, making it difficult tomaintain a sufficient plasma level of the drug without administeringlarge and frequent doses of the drug. In clinical practice, one 200 mgtablet is often administered with each LD/CD or LD/Benserazide dose. Themaximum recommended dose is 200 mg ten times daily, i.e., 2,000 mg.Continuous oral administration of Entacapone could reduce the dosageand/or frequency of administration of the drug and its side effects. Thereduced dosage could alleviate side effects such as dyskinesia and/orgastrointestinal problems, nausea, abdominal pain or diarrhea.

Entacapone could be continuously orally administered in a daily dose ofless than 1000 mg per 16 hours while the patient is awake (such as lessthan 500 mg per 16 awake hours), for example as an aqueous suspensionincluding small particles, e.g., less than 100 μm average diameter, suchas less than 30 μm, 10 μm, 3 μm or 1 μm particles of Entacapone.Alternatively, it could be administered as a suspension in a non-aqueoussolution, such an edible oil, cocoa-butter, propylene glycol, orglycerol.

Tolcapone is a reversible COMT inhibitor of 2-3 hour half-life. Itexerts its COMT inhibitory effects in the central nervous system as wellas in the periphery. Its use is limited by its hepatotoxicity. Thetypical dose of Tolcapone in PD management is 100-200 mg three timesdaily. Tolcapone may also be effective in the treatment of HallucinogenPersisting Perception Disorder, decreasing visual symptoms. Continuousoral administration of Tolcapone could reduce its dosage and/orfrequency of administration and its hepatotoxicity. The reduced dosagecould alleviate its hepatotoxicity. Its daily dose could be less than500 mg per 16 awake hours, such as less than 300 mg per 16 awake hours.It could be continuously orally administered, for example, as asuspension of the invention including small particles, e.g., less than100 μm average diameter, such as less than 30 μm, 10 μm, 3 μm or 1 μmparticles of the drug.

Because administration according to this invention is typically into themouth, it is preferred that the drugs selected for administration arethose whose taste is neutral or pleasant, as perceived by a majority ofpatients. Taste masking or modifying excipients may be added to theformulations of drugs whose taste is unpleasant, as perceived by amajority of patients.

Other drugs that may usefully be delivered in accordance with theinvention include methylphenidate, prostaglandins, prostacyclin,treprostinil, beraprost, nimodipine, and testosterone.

Examples of drugs that are often prescribed to be dosed four times perday include:

-   -   Amoxicillin—infection    -   Cephalexin (Keflex)—infection    -   Chlorpromazine (Thorazine)—neuroleptic for migraine    -   Diazepam (Valium)—anxiety and sleep    -   Diclofenac (Voltaren)—arthritis    -   Diltiazem—calcium channel blocker    -   Erythromycin—infection    -   Holperiodol (Haldol)—neuroleptic for migraine    -   Impramine—psychotropic    -   Ipratropium (Atrovent)—Anticholinergic    -   Metoclopramide (Reglan)—gastroesophageal reflux, migraine    -   Niledpine—calcium channel blocker    -   Olanzapine (Zyprexa)—neuroleptic for migraine    -   Prochlorperazine (Compazine)—neuroleptic for migraine    -   Promethazine (phenergan)—neuroleptic for migraine    -   Salbutamolasthma    -   Tetracycline—infection    -   Theophylline (Theolair)—COPD, asthma    -   Trazodone—psychotropic

Drugs delivered as solids may be formulated with excipients to increasedisintegration or dispersion.

Many types of drugs may be delivered in accordance with the invention.Drugs which may in principle be used for treatment according to theinvention are any known drugs, wherein the drugs may be present in theform according to the invention as such, or in the form of the activeingredient, optionally in the form of a pharmaceutically acceptable saltof the active ingredient. Drugs which may be delivered in accordancewith the invention include, without limitation, analgesics andantiinflammatory agents (e.g., aloxiprin, auranofin, azapropazone,benorylate, diflunisal, etodolac, fenbufen, fenoprofen calcim,flurbiprofen, ibuprofen, indomethacin, ketoprofen, meclofenamic acid,mefenamic acid, nabumetone, naproxen, oxyphenbutazone, phenylbutazone,piroxicam, sulindac), antihelmintics (e.g., albendazole, bepheniumhydroxynaphthoate, cambendazole, dichlorophen, ivermectin, mebendazole,oxamniquine, oxfendazole, oxantel embonate, praziquantel, pyrantelembonate, thiabendazole), anti-arrhythmic agents (e.g., amiodarone HCl,disopyramide, flecainide acetate, quinidine sulphate, anti-bacterialagents (e.g., benethamine penicillin, cinoxacin, ciprofloxacin HCl,clarithromycin, clofazimine, cloxacillin, demeclocycline, doxycycline,erythromycin, ethionamide, imipenem, nalidixic acid, nitrofurantoin,rifampicin, spiramycin, sulphabenzamide, sulphadoxine, sulphamerazine,sulphacetamide, sulphadiazine, sulphafurazole, sulphamethoxazole,sulphapyridine, tetracycline, trimethoprim), anti-coagulants (e.g.,dicoumarol, dipyridamole, nicoumalone, phenindione), antidepressants(e.g., amoxapine, maprotiline HCl, mianserin HCl, nortriptyline HCl,trazodone HCl, trimipramine maleate), antidiabetics (e.g.,acetohexamide, chlorpropamide, glibenclamide, gliclazide, glipizide,tolazamide, tolbutamide), anti-epileptics (e.g., beclamide,carbamazepine, clonazepam, ethotoin, methoin, methsuximide,methylphenobarbitone, oxcarbazepine, paramethadione, phenacemide,phenobarbitone, phenytoin, phensuximide, primidone, sulthiame, valproicacid, topirimate, lamotrigine, gabapentin, levetiracetam, pregabalin),antifungal agents (e.g., amphotericin, butoconazole nitrate,clotrimazole, econazole nitrate, fluconazole, flucytosine, griseofulvin,itraconazole, ketoconazole, miconazole, natamycin, nystatin, sulconazolenitrate, terbinafine HCl, terconazole, tioconazole, undecenoic acid),antigout agents (e.g., allopurinol, probenecid, sulphin-pyrazone),antihypertensive agents (e.g., amlodipine, benidipine, darodipine,dilitazem HCl, diazoxide, felodipine, guanabenz acetate, isradipine,minoxidil, nicardipine HCl, nifedipine, nimodipine, phenoxybenzamineHCl, prazosin HCl, reserpine, terazosin HCl), antimalarials (e.g.,amodiaquine, chloroquine, chlorproguanil HCl, halofantrine HCl,mefloquine HCl, proguanil HCl, pyrimethamine, quinine sulphate),anti-migraine agents (e.g., dihydroergotamine mesylate, ergotaminetartrate, methysergide maleate, pizotifen maleate, sumatriptansuccinate), anti-muscarinic agents (e.g., atropine, benzhexol HCl,biperiden, ethopropazine HCl, hyoscyamine, mepenzolate bromide,oxyphencylcimine HCl, tropicamide), anti-neoplastic agents andimmunosuppressants (e.g., aminoglutethimide, amsacrine, azathioprine,busulphan, chlorambucil, cyclosporin, dacarbazine, estramustine,etoposide, lomustine, melphalan, mercaptopurine, methotrexate,mitomycin, mitotane, mitozantrone, procarbazine HCl, tamoxifen citrate,testolactone), anti-protazoal agents (e.g., benznidazole, clioquinol,decoquinate, diiodohydroxyquinoline, diloxanide furoate, dinitolmide,furzolidone, metronidazole, nimorazole, nitrofurazone, ornidazole,tinidazole), anti-thyroid agents (e.g., carbimazole, propylthiouracil),anxiolytic, sedatives, hypnotics and neuroleptics (e.g., alprazolam,amylobarbitone, barbitone, bentazepam, bromazepam, bromperidol,brotizolam, butobarbitone, carbromal, chlordiazepoxide, chlormethiazole,chlorpromazine, clobazam, clotiazepam, clozapine, diazepam, droperidol,ethinamate, flunanisone, flunitrazepam, fluopromazine, flupenthixoldecanoate, fluphenazine decanoate, flurazepam, haloperidol, lorazepam,lormetazepam, medazepam, meprobamate, methaqualone, midazolam,nitrazepam, oxazepam, pentobarbitone, perphenazine pimozide,prochlorperazine, sulpiride, temazepam, thioridazine, triazolam,zopiclone), β-Blockers (e.g., acebutolol, alprenolol, atenolol,labetalol, metoprolol, nadolol, oxprenolol, pindolol, propranolol),cardiac inotropic agents (e.g., amrinone, digitoxin, digoxin, enoximone,lanatoside C, medigoxin), corticosteroids (e.g., beclomethasone,betamethasone, budesonide, cortisone acetate, desoxymethasone,dexamethasone, fludrocortisone acetate, flunisolide, flucortolone,fluticasone propionate, hydrocortisone, methylprednisolone,prednisolone, prednisone, triamcinolone), diuretics: acetazolamide,amiloride, bendrofluazide, bumetanide, chlorothiazide, chlorthalidone,ethacrynic acid, frusemide, metolazone, spironolactone, triamterene),anti-parkinsonian agents (e.g., bromocriptine mesylate, lysuridemaleate), gastrointestinal agents (e.g., bisacodyl, cimetidine,cisapride, diphenoxylate HCl, domperidone, famotidine, loperamide,mesalazine, nizatidine, omeprazole, ondansetron HCl, ranitidine HCl,sulphasalazine), histamine H,-receptor antagonists (e.g., acrivastine,astemizole, cinnarizine, cyclizine, cyproheptadine HCl, dimenhydrinate,flunarizine HCl, loratadine, meclozine HCl, oxatomide, terfenadine),lipid regulating agents (e.g., bezafibrate, clofibrate, fenofibrate,gemfibrozil, probucol), nitrates and other anti-anginal agents (e.g.,amyl nitrate, glyceryl trinitrate, isosorbide dinitrate, isosorbidemononitrate, pentaerythritol tetranitrate), opioid analgesics (e.g.,codeine, dextropropyoxyphene, diamorphine, dihydrocodeine, meptazinol,methadone, morphine, nalbuphine, pentazocine), sex hormones (e.g.,clomiphene citrate, danazol, ethinyl estradiol, medroxyprogesteroneacetate, mestranol, methyltestosterone, norethisterone, norgestrel,estradiol, conjugated oestrogens, progesterone, stanozolol, stibestrol,testosterone, tibolone), and stimulants (e.g., amphetamine,dexamphetamine, dexfenfluramine, fenfluramine, mazindol).

The above-stated compounds are predominantly stated by theirinternational nonproprietary name (INN) and are known to the personskilled in the art. Further details may be found, for example, byreferring to International Nonproprietary Names (INN) for PharmaceuticalSubstances, World Health Organization (WHO).

Gastroparesis, delayed or erratic gastric emptying, and otherabnormalities or diseases of the stomach, intestine, pylorus, jejunum,duodenum impact the transport of food and medication from the stomach tothe duodenum and through the small and large intestines. Such conditionsof the GI tract are commonly caused by or associated with variousdiseases and conditions, including Parkinson's disease, diabetes,autonomic neuropathy, and cancer treatments. Reduced, delayed, orerratic transport of medication from the stomach to the duodenum andthrough the small and large intestines decreases the benefits oreffectiveness of many drugs, including levodopa. It is for this reasonthat the Duopa™ (also known as Duodopa™) LD/CD delivery system infuses aLD/CD suspension into the jejunum or duodenum, even though intrajejunaldelivery requires surgical implantation of a PEG tube and suffers from ahigh rate of PEG tube related complications. The inventors discoveredthat the oral intake of an aqueous solution of L-DOPA and carbidopa atfrequency of about 6-12 times/hour also stabilizes the plasmaconcentration of L-DOPA and reduces by about 43% the OFF time of PDpatients. Without limiting the scope of this invention by a theory ormodel, we have observed that the reported gastric delay of drugs doesnot necessarily apply when the drugs are continuously orally infused andare dissolved. Thus, it can be advantageous to infuse into the mouths ofpatients a suspension or paste including solid drug particles at a ratethat equals or is slower than the rate of dissolution of the solid drugparticles in body fluids secreted in the mouth, such that the drugpassing through the esophagus to the stomach is already substantiallydissolved, such that the remaining solid drug particles aresubstantially dissolved in fluid secreted in the stomach, and/or suchthat the still remaining drug particles are substantially dissolved influid secreted in the duodenum, then, if solid drug particles stillremain, these are substantially dissolved in fluids secreted in thejejunum, then if still present, substantially dissolved in fluidssecreted in the ileum, and eventually if still present, substantiallydissolved in fluids secreted in the colon. The secreted body fluid inwhich the solid drug may dissolve can be, for example, saliva secretedin the mouth (e.g., by the submandibular and parotid glands) mostly inthe awake hours. In healthy persons the rate of secretion can be betweenabout 50 mL/hour and about 100 mL/hour. Considering that the solubilityof LD can be about 50 mg/mL and considering that even if a patient wouldrequire as much as 200 mg LD per hour, as little as about 4 mL/hour ofsaliva could dissolve the orally delivered solid LD. The drug could notonly be dissolved, but its solution might be diluted before reaching thestomach even in patients (e.g., patients with PD or xerostomia)secreting less saliva than healthy people. For rapid dissolution insaliva it could be advantageous to disperse the drug particles (e.g., byadministering their surfactant-including suspension) where the size ofthe drug particles could be small (e.g., typically less than about 100μm in average diameter, such as less than 50 μm in average diameter,such as less than 20 μm in average diameter, such as less than 10 μm inaverage diameter).

Other drugs, such as baclofen or pyridostigmine, that are administeredin lesser daily amounts than LD could be adsorbed on small particles ofa solid excipient, such as an amino acid like tyrosine. For continuousoral delivery, the paste of the drug-containing excipient could beextruded into the mouth where the excreted saliva would dissolve thesorbed drug as well as any solid drug particles, if present.

Drug Delivery Devices

The drug delivery devices of the present invention are designed toaddress the requirements for a device that is inserted into the mouth bythe patient or caregiver, and that resides in the mouth while it isadministering drug, and that can be removed from the mouth by thepatient or caregiver. Preferred drug delivery devices include oralliquid impermeable reservoirs.

The drug delivery devices typically have a total volume of less thanabout 10 mL, and preferably less than 7.5, 5.0, or 3.0 mL. Preferredvolumes for the drug delivery devices are 0.5-3.0 mL, to minimizeinterference with the patient's mastication, swallowing and speech.

The drug delivery devices of the invention preferably containbite-resistant structural supports that enable them to withstand apatient's bite with a force of at least 200 Newtons, without rupturingand without infusing a bolus of greater than 5% of the drug contents,when unused reservoirs are newly inserted into the mouth. Bite-resistantstructural supports, for example, can include a structural housing thatencapsulates the entire drug reservoir, propellant reservoir and pumpcomponents, either protecting individual components, the entire device,or both. Structural housings can be constructed of any tough,impact-resistant, material that is compatible with the oral anatomy.Metals such as stainless steel or titanium, composites, optionally fiberreinforced polymers such as poly (methyl methacrylate) and strongpolymers such as Kevlar, are examples of tough materials that arecompatible with the oral anatomy. Other structural elements can includeposts or ribs in the housings that are placed in locations such thatcompression is not possible due to the stiffness of the housingcomponents being increased. In another example, structural elements,such as ribs and posts, allow some flexure of the housing, but do notallow sufficient flexure to deform the components of the pump. Inanother example, the pump housing can be made of a material that allowssome flexure and there is sufficient volume within the housing such thatthe drug reservoir and or propellant reservoir, can deform or becomedisplaced when pressure is applied but maintain their structuralintegrity. In another embodiment, some of the previously describedelements can be incorporated into a design, and the entire internalvolume of the device can be potted with a tough biocompatible materialsuch as an epoxy or a thermoplastic.

To prevent their being accidentally swallowed or aspirated into thetrachea, the drug delivery devices of the invention are either securedin the mouth or are of a shape and size that cannot be swallowed oraspirated into the trachea. They may be secured to any interior surfaceof the mouth, such as one or more teeth, the roof of the mouth, thegums, the lips or the cheek within the mouth of the patient. In order toobtain a secure and comfortable fit, the devices may be molded to fit onor attach to a surface within the mouth of a patient, such as the teethor the roof of the mouth, or they may conform to at least one cheek. Insome embodiments, the drug delivery devices are secured such that theyare positioned on the teeth, on a cheek, between the gums and the cheek,between the gums and the lips, or at the roof of the mouth.Alternatively, the drug delivery device includes a shape and size thatcannot be swallowed. Examples are a curved, elongated shape of greaterthan 4 cm length in its curved form (e.g., greater than 5, 6 or 7 cm)that can be placed between the gums and the cheek and lips; or drugdelivery devices positioned adjacent to both cheeks and connected with abridge, optionally forming fluidic contacts with both the left and theright parts.

Although the housing of the typical drug delivery device of theinvention can be a strong material such as a metal or a ceramic, thedevice may include in some embodiments a rigid plastic, a strongelastomer, a deformable plastic or a plastic that optionally deformssuch that it can conform to contours of the mouth of the patient (forexample, to contours of the cheek, or of the roof mouth, or the floor ofthe mouth, or the front gum near a lip, or the teeth). The plastic mayoptionally be fiber reinforced, i.e., it may be re-inforced, forexample, by carbon, metal, glass fibers, or by fibers of a strongpolymer, such as a polyimide. The plastic may include, for example,elastomeric butyl rubber, elastomeric silicone or polyurethane. It canbe a less deformable, for example substantially oxygen or waterimpermeable, plastic, such as poly(vinylidene chloride), poly(vinylchloride), poly(triflurorochloro)ethylene, poly(ethyleneterephthalate)), polyether polycarbonate, or high density, highcrystallinity polyethylene. Alternatively, the drug delivery device mayinclude a metal, such as stainless steel or alloyed titanium, aluminumor magnesium. In an alternative embodiment, the drug delivery deviceincludes multiple segments connected by flexible connectors, so that thedrug delivery device is able to conform to the shape of the surface onwhich it is mounted.

The drug delivery devices of the invention may be attached to the teethor other interior surfaces of the mouth by a fastener, as shown in FIGS.1A and 1B. The fastener 1, the one or more pumps 2, and the one or moredrug reservoirs 3 may include a single unit or they may include separatecomponents, with the fastener remaining in the mouth when the one ormore pumps or one or more reservoirs are removed. FIG. 1A shows anembodiment where a pump 2, and a drug reservoir 3 include a singleremovable component that can be attached to the fastener 1. Drug isdelivered into the mouth via a tube 5 which may optionally include aflow restrictor. FIG. 1B shows an embodiment including a reusablehousing 4, and a disposable pump 2 and drug reservoir 3. The fastener 1,one or more drug pumps and one or more drug reservoirs may be removablyattached to each other using magnets, clips, clasps, clamps, flanges,latches, retaining rings, snap fasteners, screw mounts, or otherattachment mechanisms known in the art. In preferred embodiments, thefastener includes a transparent retainer or a partial retainer on oneside of the mouth (e.g., attached to 3, 4, or 5 teeth). FIG. 1C depictsan embodiment in which a pump 2 and a drug reservoir 3 form a singlecomponent.

An embodiment of the device is shown in FIGS. 2A and 2B, where the pumpand/or oral liquid impermeable reservoir is secured to either the upperor lower teeth using a transparent retainer 6. One, two or more pumpsand/or one or more drug reservoirs are secured on the buccal side of thetransparent retainer. One, two, or more drug pumps 2 and/or drugreservoirs 3 may be secured unilaterally, on either the right or leftsides, positioned in the buccal vestibule or, alternatively, on thelingual side of the teeth. The drug pump and reservoir are attached tothe transparent retainer via a housing 4. Drug is delivered into themouth via a tube 5 which may optionally include a flow restrictor. Thetube 5 serves to carry the drug from the buccal to the lingual side ofthe teeth, where the drug may be more readily swallowed. The tube may bemolded into the retainer.

In a related embodiment, illustrated in FIG. 3, the pumps 2 andreservoirs 3 can be configured to be positioned both on the lingual sideof the teeth and in the buccal vestibule. In this embodiment, the pump 2is used to fill an expandable polymeric (e.g., elastomeric ornon-elastomeric) compartment 7, described in greater detail in FIGS.11A, 11B, and 11C, which drives the drug from the drug reservoir 3. Inanother related embodiment, illustrated in FIGS. 4A and 4B, one, two ormore pumps and/or oral liquid impermeable reservoirs may be securedbilaterally, on both the right and left sides, positioned in the buccalvestibule or on the lingual side of the teeth, or both buccally andlingually. FIG. 4A depicts a fastener in the form of an invisibleretainer 6, including two bilateral housings 4 (shown empty) on thebuccal side of the teeth into which drug pumps and/or drug reservoirsmay be inserted. FIG. 4B depicts a fastener in the form of an invisibleretainer 6, including two bilateral housings 4 (shown filled) on thelingual side of the teeth into which drug pumps and/or drug reservoirshave been inserted.

Optionally, two or more oral liquid impermeable drug reservoirs may bein fluidic contact with each other. Optionally, the transparent retainer6 may include 2, 3, 4 or more layers of different hardness, to easeinsertion and removal of the transparent retainer from the teeth. Forexample, the transparent retainer 6 may include a dual laminate with asofter, inner, tooth-contacting layer, and a harder, outer layercontacting the cheeks and tongue.

The one or more pumps and/or oral liquid impermeable reservoirs may beremovably attached to the transparent retainer using magnets, clips,clasps, clamps, flanges, latches, retaining rings, snap fasteners, screwmounts, or other attachment mechanisms known in the art. In oneembodiment, the transparent retainer includes one, two, or more housingsinto which one, two, or more pumps and/or the oral liquid impermeablereservoir are inserted. The one, two or more housings may be molded orformed to the shape of the one, two or more pumps and/or oral liquidimpermeable reservoirs.

For delivery of some drugs, such as LD or CD, it can be desirable toadminister the drug-including solid or fluid on the lingual side of theteeth, rather than on the buccal side of the teeth, in order to minimizethe residence time of the drug in the mouth, thereby avoiding potentialaccumulation of the drug in the buccal vestibule and minimizingpotentially irritating exposure of the buccal tissue to the drug. In apreferred embodiment, the fastener (e.g., a transparent retainer or apartial retainer) includes one, two, or more fluidic channels totransport the drug-including fluid into the mouth from the one, two ormore pumps and/or oral liquid impermeable reservoirs. The fluidicchannels can transport the drug-including fluid from one, two, or moreoral liquid impermeable reservoirs located on the buccal side of theteeth to the lingual side of the teeth. For example, the fluidicchannels can include one, two or more tubes that are molded into thefastener. The fluidic channels can, for example, pass behind the rearmolars, above the mandibular arch, so that they do not cross the bitingsurface of the teeth. The fluidic channels may include an inner diameterof less than 0.25 mm, 0.25-1 mm, 1-2 mm, 2-3 mm, or greater than 3 mm.The fluidic channels may include a fluidic path length in the fastenerof less than 1 mm, 1-3 mm, 3-5 mm, 5-10 mm, or greater than 10 mm, suchas 1-2 cm, 2-3 cm or 3-4 cm.

The one, two or more pumps and/or one, two, or more oral liquidimpermeable drug reservoirs can be in fluid communication with the one,two, or more fluidic channels in the fastener (e.g., a transparentretainer or a partial retainer) via any type of leak-free fluidicconnector known in the art, such as leak-free snap fastener orscrew-mount. The leak-free fluidic connector preferably includes metal,to improve durability. Optionally, the one, two or more pumps and/or theone, two, or more oral liquid impermeable reservoirs do not deliver drugwhen they are not mounted on the fastener, while mounting these on thefastener initiates delivery of the drug. Similarly, drug delivery can betemporarily halted when the pumps and/or oral liquid impermeablereservoirs are dismounted from the fastener.

In one embodiment, the one, two or more fluidic channels may includeone, two or more flow restrictors. The one, two or more flow restrictorsmay include metal tubes that are molded into the fastener (e.g., atransparent retainer or a partial retainer). By incorporating flowrestrictors into a reusable fastener, the disposable drug deliverydevice and/or oral liquid impermeable reservoir need not include a flowrestrictor that accurately controls the rate of infusion.

In another embodiment, a reusable fastener (e.g., a transparent retaineror a partial retainer) may include a pump and/or power source. With areusable pump and/or power source incorporated into the fastener, thedisposable portion of the drug delivery device and/or the oral liquidimpermeable reservoir need not include the pump and/or power source,thereby reducing overall cost. For example, the fastener may include apiezoelectric or battery driven electroosmotic pump, and/or a battery.The battery may optionally be rechargeable.

The fastener or its components, such as the housings, may bemanufactured using methods known in the art, such as thermoforming,injection molding, pressure molding, and laminating.

The drug delivery device may be a single unit, or it may have two,three, four, five or more components. The drug delivery device may haveone, two, three, four, five or more oral liquid impermeable reservoirsin which the solid or fluid drug formulation is contained. These one ormore reservoirs may form a single component, or they may form multiplecomponents.

The drug delivery devices may be reusable, disposable, or they may haveone or more reusable components and one or more disposable components.In a preferred embodiment, the fastener is reusable, and may be reusedfor a period of equal to or greater than 7, 30, 60 or 180 days, or oneyear or two years. In another preferred embodiment, the one or more oralliquid impermeable reservoirs are single use, disposable components. Thepump may be either reusable or disposable. A flow restrictor, ifpresent, may be a single use disposable or may be reused.

The oral liquid impermeable reservoir may be refillable with a solid orfluid drug formulation. In a preferred embodiment, the oral liquidimpermeable reservoir is a single use disposable. The oral liquidimpermeable reservoir may be filled by the user. In preferredembodiments, the oral liquid impermeable reservoir is prefilled.

The drug delivery device further includes one, two, three, four or moreorifices for releasing the drug from the device into the mouth.

Durations of administration from a single drug delivery device or oralliquid impermeable reservoir typically exceed 4, 8, 12, or 16 hours perday, up to and including 24 hours per day. Administration can also takeplace over multiple days from a single device or oral liquid impermeablereservoir, e.g., administration of a drug for 2 or more days, 4 or moredays, or 7 or more days. The devices can be designed such that they canbe worn when the patient is awake or asleep.

It is desirable that the patient be able to temporarily remove the drugdelivery device from the mouth, for example, to eat meals, brush teeth,or at times when the patient does not want or need the medication (e.g.,at night). Consequently, the drug delivery devices and/or some of itscomponents (such as the pump and/or the oral liquid impermeablereservoirs) can be temporarily removable. It is, however, acceptable forsome components, such as the fastener, to remain in the mouth if thesedo not interfere with the patient's activities. For example, a band, afastener cemented or glued to one or more teeth, a retainer, or amuco-adhesive patch adhered to the oral mucosa, and which holds the pumpand/or oral liquid impermeable reservoir in place, may remain in themouth when the pump and/or the oral liquid impermeable reservoir areremoved.

The drug delivery device preferably can have a shape that is comfortablein the mouth. Typically such a shape has rounded edges. Shapes such asobround shapes are typically more comfortable than cylindrical shapes.

It is desirable that the drug delivery device include an indicator of:the quantity remaining of one or more drugs; the infusion time remaininguntil empty; and/or that one or more of the oral liquid impermeablereservoirs is empty and should be replaced.

The drug delivery devices of the current invention are configured andarranged to administer one or more solid or fluid drug formulations fromone or more oral liquid impermeable reservoirs including a total volumeof 0.1-10 mL of drugs, e.g., 0.1-1.0, 1.0-2.0, 2.0-3.0, 3.0-4.0,4.0-5.0, 5.0-6.0, 6.0-7.0, 7.0-8.0, 8.0-9.0, or 9.0-10 mL. They areconfigured and arranged to administer the one or more solid or fluiddrug formulations at a rate in the range of 0.03-1.25 mL/hour, e.g.,0.03-0.10, 0.10-0.20, 0.20-0.30, 0.30-0.40, 0.40-0.50, 0.50-0.60,0.60-0.70, 0.70-0.80, 0.80-0.90, 0.90-1.0, 1.0-1.1, or 1.1-1.25 mL/hour.In some embodiments, they are configured and arranged to administer thedrug, (i.e., the active pharmaceutical ingredient) at an average rate of0.01-1 mg per hour, 1-10 mg per hour, 10-100 mg per hour, or greaterthan 100 mg per hour. In other embodiments, the drug product (i.e., theactive pharmaceutical ingredient plus excipients) is delivered at anaverage rate of 0.01-1 mg per hour, 1-10 mg per hour, 10-100 mg per houror greater than 100 mg per hour.

The one or more drugs may be administered at a constant rate or at anon-constant rate that varies over the course of the administrationperiod. For example, the drug delivery device may be programmed toadminister drugs according to a drug delivery profile over the course ofthe administration period. The drug delivery device may also have anon-demand bolus capability, whereby the patient or caregiver mayinitiate the delivery of a bolus of drug.

In preferred embodiments, the drug delivery device administers one ormore solid or fluid drug formulations via continuous and/or frequentadministration, e.g., infusion. In a preferred embodiment, the solid orfluid drug administration rate is held constant or near constant for aperiod of 4, 8, 12, 16 or 24 hours during the day. For example, theadministered volume may vary by less than ±10% or ±20% per hour, or by±10% or ±20% per 15 minute period, over a period of 4, 8, 12, 16 or 24hours. In another embodiment, the solid or fluid drug administrationrate is held about constant during the awake hours of the day. Inanother embodiment, the solid or fluid drug formulation administrationrate is held about constant during the asleep hours. In anotherembodiment, the solid or fluid drug formulation administration rate isheld about constant during the awake hours of the day, except for thedelivery of a bolus at about the time of waking. In one embodiment, theadministration rate can be set prior to insertion in the mouth by thepatient or by the caregiver. In another embodiment, the administrationis semi-continuous and the period between the infusions is less than thebiological half-life of the drug t_(1/2); for example it can be lessthan one half of t_(1/2), less than ⅓rd of t_(1/2), or less than ¼ oft_(1/2), or less than 1/10th of t_(1/2).

For fluid drug formulations, it is desirable to deliver the solutions orsuspensions of the invention using drug delivery devices that are small,efficient, inexpensive, and reliable. This can be particularlychallenging when these fluids are viscous. It is also desirable tominimize the pressure required to pump the fluid. In preferred drugdelivery devices for fluids of greater than 100 cP, for example,100-1000 cP, 1,000-10,000 cP, 10,000-100,000 cP, 100,000-500,000 cP,500,000-2,500,000 cP, or greater than 2,500,000 cP, the drug can exitthe device through a tube, nozzle, channel, or orifice of less than 4cm, 3 cm, 2 cm, 1 cm, 0.5 or 0.2 cm length. For example, the fluid maybe delivered through an optionally flexible cannula, or it may bedelivered through an orifice without utilizing any type of tubing orcannula. To further minimize the pressure required to pump the fluid,the tube, channel or orifice through which the drug exits the device mayhave an internal diameter of greater than 0.5, 1, 2, 3, 4, or 5 mm, forexample, 1 mm-5 mm, 1 mm-3 mm, 2 mm-4 mm, or 3 mm-5 mm. Preferredminimum internal diameters are 0.1-2 mm (0.1-0.7 mm, 0.2-0.5 mm,0.5-0.75 mm, 0.75-1.0 mm, 1.0-1.5 mm, or 1.5-2.0 mm) and preferredlengths are 0.25-5 cm (such as 1-2.5 cm, 1-5 cm, 0.25-0.5 cm, 0.5-0.75cm, 0.75-1 cm, 1-2 cm, 2-3 cm, 3-4 cm, or 4-5 cm).

Pumps

The pumps for the drug delivery devices must be suitable for miniaturedevices carried safely and comfortably in the mouth. Any suitable pumpmay be used. The pump and the oral liquid impermeable reservoir may bedistinct.

Miniature pumps are advantageous for placement in the mouth. Forexample, the extruded fluid including the drug may occupy more than 33%,50%, 66%, or 75% of the total volume of the drug delivery device.

Non-Electric Pumps.

Pumps that do not require a battery can be smaller and have fewer movingparts than battery-requiring electrical pumps. One group of nonelectricdisposable pumps of the invention is based on the physical principlethat mechanical restriction within the flow path can determine the flowrate of a pressurized fluid. The pressure on the fluid may be generatedby a variety of mechanisms using nonelectric power, including astretched elastomer, a compressed elastomer, a compressed spring, achemical reaction, a propellant, and a cartridge of pressurized gas. Therestriction of flow may be provided by an orifice (e.g., in the drugreservoir), by narrow-bore tubing (such as a metal, glass or plasticpipe), or by a channel, or by a capillary, or a flow-controlling nozzle.Optionally, the flow-controlling nozzles, channels or tubes can be madeof a plastic such as an engineering plastic, or made of a metal or aceramic such as a glass. The nozzles, channels or tubes can have aninternal diameter less than 1 mm, 0.6 mm, 0.3 mm or 0.1 mm and they canbe shorter than 10 cm, 5 cm, 2 cm or 1 cm such as 0.5 cm. Preferredminimum internal diameters are 0.1-2 mm (0.1-0.7 mm, 0.2-0.5 mm,0.5-0.75 mm, 0.75-1.0 mm, 1.0-1.5 mm, or 1.5-2.0 mm) and preferredlengths are 0.25-5 cm (such as 1-2.5 cm, 1-5 cm, 0.25-0.5 cm, 0.5-0.75cm, 0.75-1 cm, 1-2 cm, 2-3 cm, 3-4 cm, or 4-5 cm).

Because different patients may require different doses of drug, it isdesirable for the drug delivery devices of the invention to be availableas a product line of multiple products, each product having a differentdrug administration rate. The desired flow rate may be obtained byselecting a flow restrictor of the appropriate inner diameter andlength. In one embodiment, the plastic flow restricting nozzle or tubingmay be cut to the length providing the desired flow rate. Use of anarrow-bore tubing as a flow restrictor simplifies the manufacturingprocess for such a product line. During the manufacturing process anarrow-bore tubing with constant inner diameter may be cut into multiplesegments of fixed length A, to provide reproducible flow restrictors forproducts with one flow rate. A different portion of the narrow-boretubing with constant inner diameter may be cut into multiple segments offixed length B, to provide reproducible flow restrictors for productswith a second flow rate.

In another embodiment, when the reservoir is metallic one or morepinholes in the reservoir wall can include the flow restrictor, i.e., adesired flow rate can be obtained by the number of pinholes and thediameter of the one or more pinholes.

In yet another embodiment, the flow restrictor can include an orificewith an adjustable diameter, similar to the user-adjustable aperture ofa camera. Instead each device being able to infuse at only a singleinfusion rate such a user-adjustable orifice could allow the physicianor the patient to set the infusion rate, thereby providing moreflexibility and convenience.

The preferred nozzles, channels or tubes can be made of an engineeringplastic, can have an internal diameter less than 1 mm, 0.6 mm, 0.3 mm or0.1 mm and can be shorter than 10 cm, 5 cm, 2 cm or 1 cm such as 0.5 cm.Preferred minimum internal diameters are 0.1-2 mm (0.1-0.7 mm, 0.2-0.5mm, 0.5-0.75 mm, 0.75-1.0 mm, 1.0-1.5 mm, or 1.5-2.0 mm) and preferredlengths are 0.25-5 cm (such as 1-2.5 cm, 1-5 cm, 0.25-0.5 cm, 0.5-0.75cm, 0.75-1 cm, 1-2 cm, 2-3 cm, 3-4 cm, or 4-5 cm).

Flow rate can be affected by the pressure gradient across the flowrestrictor and by fluid viscosity. A significant source of inaccuracy inexisting pump products can be that viscosity is strongly affected bytemperature. An important benefit of carrying within the mouth the drugdelivery devices of the invention is that the temperature is held nearlyconstant at about 37° C., thereby minimizing variations in therheological properties (such as viscosity) and therefore in the infusionrate. The nearly constant about 37° C. is also advantageous inmaintaining a stable pumping pressure when a gas, such as from a liquidpropellant, is used to drive the pump.

The formulations of the invention are often viscous suspensions. Use ofviscous suspensions is often desired to achieve the small volumes, highconcentrations, uniform drug dispersion, storage stability, andoperational stability desired for the drugs and methods of theinvention. Consequently, it is often desired to employ pump mechanismsthat can provide the pressures required to pump the viscous fluids.

The pressure generated by elastomeric, spring-driven and gas-drivenpumps on fluid is typically in the range of 250 mm Hg to 5,000 mm Hg,depending on flow rate and cannula size, but can be higher. For example,the pressure may be 250-500 mm Hg, 500-750 mm Hg, 750-1,000 mm Hg,1,000-1250 mm Hg, 1,250-2,500 mm Hg, 2,500-5,000 mm Hg, or greater than5,000 mm Hg. The pressurizing gas can be a propellant that condenses toa liquid at a pressure greater than 1 bar (such from 1 bar to 2 bar,from 2 bar to 3 bar, from 3 bar to 4 bar, or from 4 bar to 5 bar atabout 37° C.), or the pressurizing gas can be chemically generated, forexample electrolytically generated, (e.g., by electrolyzing water).

The drug delivery device may be kept in the mouth while the patient iseating and drinking, or may be removed for eating or drinking.Preferably, the introduction into the mouth of food or liquid, includingfood or liquids that are hot, cold, acidic, basic, oily, or alcoholic,does not have a clinically significant effect on the drug delivery. Forexample, such conditions may affect the solubility of the drug; thevolume of the drug-including fluid in the reservoir; the viscosity ofthe drug-including fluid in the oral liquid impermeable reservoir; thevolume of the gas in the reservoir (if present); the diffusivity ofmass-transport limiting membranes (if present); and/or the force exertedby elastomers or springs (if present). Some drug delivery technologies,such as controlled release muco-adhesive drug delivery patches, candeliver large drug boluses when in contact with a hot, cold, acidic,basic, oily, or alcoholic liquid in the mouth. Such boluses may resultin undesirable clinical effects, and should be minimized. In oneembodiment, the solid or fluid drug delivery devices of the inventiondeliver a bolus of less than 5%, 4%, 3%, or 2% of the contents of afresh oral liquid impermeable reservoir when immersed for 5 minutes orfor 1 minute in a beaker containing a stirred aqueous 0.14 M salinesolution that is hot (e.g., at about 55° C.), cold (e.g., at about 1°C.), acidic (e.g., at about pH 2.5), basic (e.g., at about pH 9), oily(e.g., emulsion of 5% by weight of olive oil in 0.14 M aqueous salinesolution), or alcoholic (e.g., a 0.14 M saline solution containing 5% byweight ethanol). For example, a LD delivery device may deliver a bolusof less than 0.5, 0.25, 0.12, or 0.06 millimoles of LD under theseconditions.

Battery Powered Pumps.

Other than powering the pump, the battery can power optional electroniccontrols and communication capabilities (e.g., radio frequencyreceivers) for programmed drug delivery and remote control of the drugdelivery by a transmitting device. A miniature battery may be used todrive the pump or dispensing mechanism for the delivery of the solid orfluid drug. Any low power pump drive mechanism known in the art may beused, such as syringe, hydraulic, gear, rotary vane, screw, bent axis,axial piston, radial piston, peristaltic, magnetic, piezoelectric,electroosmotic, diaphragm and memory alloy, such as nitinol, based.

An advantage of battery powered pumps for use in the mouth is that it ispossible to temporarily stop the drug delivery from the device if thepatient wishes to temporarily remove the drug delivery device from themouth. This can be accomplished, for example, by turning off theelectric power to the pump.

One embodiment of a battery powered pump is a miniature diaphragm pumpthat uses the motion of a piezoelectric crystal to fill a chamber withdrug from a reservoir in one motion and to expel the drug from thechamber in the opposite motion. Typically, the frequency of oscillationof the piezoelectric crystal is less than about 20,000 Hz, 5,000 Hz, or1,000 Hz, so as to avoid the higher frequencies where biologicalmembranes are ultrasonically disrupted or where free radicals are morelikely to be generated through a sonochemical process. A significantadvantage to the diaphragm pump is that it can be used to veryaccurately deliver materials of both high and low viscosity, as well assolids such as granules or powders.

Another embodiment of a battery powered pump is a miniatureelectroosmotic pump as disclosed, for example, in U.S. PatentPublication Nos. 2013/0041353, 2013/0156615, 2013/0153797 and2013/0153425, in PCT Publication No. WO2011/112723, and in Korean PatentPublication No. KR101305149, each of which is incorporated herein byreference. Typically the volume of the miniature electroosmotic pump,including its battery or batteries, is smaller than the volume of thefluid in the unused oral liquid impermeable reservoir. For example, thevolume of the pump can be less than half, less than ⅓^(rd), less than¼^(th), or less than ⅕^(th) of the volume of the unused oral liquidimpermeable reservoir. When an electroosmotic pump is used with arefillable reservoir, the battery powering the pump can be replaced uponrefilling. To provide different patients with different dose rates, oralliquid impermeable reservoirs may be filled with the drug at differentconcentrations. Alternatively, the flow rate of the electroosmotic pumpcan be adjusted by controlling the applied voltage or the appliedcurrent, or by varying the cross sectional fluid contacting area of themembrane sandwiched between the electrodes. Optionally, the appliedvoltage or current can be remotely adjusted by incorporating a shortrange RF receiver in the insert.

Another category of battery powered pumps is that of positivedisplacement pumps. Two examples of battery powered positivedisplacement pumps that can be used to deliver the drug are gear pumpsand peristaltic pumps. One of the main advantages of the use of apositive displacement pump is that the delivery rate is not affected bychanges in ambient pressure. The gear pump, in one embodiment, uses tworotors that are eccentrically mounted and intermeshed with their cycloidgearing. As a result a system of several sealed chambers exists at alltimes and are moved toward the outlet of the pump, one at a time. Anexample of a gear pump is the Micro annular gear pump mzr-2521 from HNPMikrosysteme GmbH. A second type of battery powered positivedisplacement pump is the peristaltic pump. Peristaltic pumps use aseries of rollers to pinch a tube creating a vacuum to draw the materialfrom a reservoir, thereby creating and moving a volume of drug withinsubsequent roller volumes to deliver the drug toward the outlet of thepump. An example of a battery powered peristaltic pump is the RP-TXseries micro peristaltic pump from Takasago Electric, Inc.

Elastomeric Infusion Pumps.

In elastomeric infusion pumps, the pressure on the fluid is generated bythe force of a stretched or compressed elastomer. An example of anelastomeric, partially disposable, constant-rate medication infusionpump with flow restrictor is the CeQur PaQ insulin patch pump, describedin U.S. Ser. No. 12/374,054 and U.S. Pat. No. 8,547,239, eachincorporated herein by reference.

FIGS. 5A and 5B show an embodiment of an elastomeric drug reservoir thatcan be filled with a drug to pressurize the drug and to pump the fluidat a controlled rate through the use of a narrow-bore tubing 8 thatserves as a flow restrictor. FIG. 5A shows the elastomeric reservoir 9when empty of drug and FIG. 5B shows the elastomeric balloon 9 whenpressurized due to expansion of the elastomer by filling with the drug.

Preferably, the elastomeric membrane is protected by an outer protectiveshell. The outer protective shell can either be a conformable elastomeror a more rigid plastic, which may be molded to a surface of the mouth.The membranes of elastomeric pumps may include both natural andsynthetic (e.g., thermoplastic) elastomers (e.g., isoprene rubber,neoprene, latex, silicon, and polyurethanes), and can be made of asingle or multiple layers. The type of elastomer and the geometry of theelastomeric balloon 9 determine the pressure generated on the fluid whenthe balloon is stretched. Multiple-layer elastomeric membranes cangenerate higher pressures than the single-layer membranes. Higherdriving pressures are of benefit for achieving faster flow rates and forpumping viscous fluids.

To minimize the change in flow rate as the fluid is delivered, it ispreferred to utilize sufficiently high tension in the elastomericmembrane such that the difference between the starting and endingpressure on the fluid is less than 30%, 20%, or 10% of the startingpressure.

Another embodiment of an elastomer-driven pump is the use of anelastomeric band 10 (e.g., a rubber band, see FIGS. 5C and 5D) to applya constant force to a drug reservoir 3 driving the drug through a narrowbore tubing 8 with a check valve 16 (or one-way valve) at the downstreamend. Elastomers are known to have material properties where large strainvalues can be imparted on them with relatively small changes in stressand, in some regions of the stress-strain curve with very little changein stress. In one embodiment of an elastomeric band pump, a stretchedpolyisoprene band is used. Polyisoprene has desirable materialproperties in that, within a specific region of the stress-strain curve,significant changes in strain result in virtually no change in stress.In this embodiment, the elastomeric rubber band 10 is used within therange in the stress-strain curve where the stress remains within theelastic region from the beginning to the end of the stroke of the motionof the piston. In this embodiment, one end of the elastomeric band 10 isplaced onto the post 12 attached to the piston 13 while the other end isplaced onto the stationary post 14. The tension on the elastomeric band10 applies a force to the drug reservoir and in order to eliminate theeffect of ambient pressure differences, a vent hole 15 allows the drugreservoir 3 to be exposed, on all sides, to ambient pressure. The checkvalve 16 also serves to keep saliva from entering the narrow bore tubing8 while the drug is not flowing. FIGS. 5C and 5D show the device with afull drug reservoir 3 and a partially emptied drug reservoir 3,respectively.

Yet another embodiment of a nonelectric disposable pump including apressurized fluid and a flow restrictor involves the use of a volume ofelastomer in a fixed volume drug reservoir. The elastomer may,optionally, be a closed cell elastomer. The elastomer can be compressedand the subsequent controlled expansion of the elastomer provides theforce to deliver the drug. In continuous pumping using a gas-includingclosed-cell elastomer, a drug-including fluid is pumped at an aboutconstant flow rate by maintaining in the fixed volume, oral liquidimpermeable reservoir an about constant pressure. For maintaining theabout constant pressure in the reservoir a substantially compressibleelastomer is placed in the reservoir. The substantially compressibleelastomer can be compressed by applying a pressure in the reservoir thatis typically less than about 100 bar (for example less than 10 bar) to avolume of elastomeric material. The volume of the compressed elastomericmaterial in the pressurized reservoir can be less than about 67%, 50%,or 25% of the volume of the elastomer at about sea-level atmosphericpressure. An exemplary family of such compressible elastomers includesclosed cell rubbers, also known as closed-cell rubber foams. Closed cellrubbers have fully rubber-enclosed gas pores, the pores containing agas, such as N₂, CO₂, or air. At about sea-level atmospheric pressurethe density of the closed pore elastomer can be less than 67% of thedensity of the elastomer without the gas, for example between 67% and33% of the elastomer without the gas, between 33% and 25% of theelastomer without the gas, between 25% and 12% of the elastomer withoutthe gas, or less than 12% of the density of the elastomer without thegas. The volume percent of the gas in the elastomer at about sea-levelatmospheric pressure can be greater than 20 volume %, for examplegreater than 50 volume %, or greater than 75 volume %. The elongation ofthe gas-including elastomer can be greater than about 25%, for examplebetween 50% and 200%, between 200% and 450%, or greater than 450%. Thegas containing elastomer can be of any shape fitting in the fixed volumedrug reservoir. It can be a single piece, such as a block, or anoptionally folded sheet, or it can be multiple pieces, such as smallgas-filled spheres. Typical gas pore enclosing elastomers can includecross-linked polymers and copolymers, for example of dienes (exemplifiedby isoprene, chloroprene (neoprene), butadiene); exemplary copolymersinclude acrylonitrile-butadiene-styrene, acrylonitrile-butadiene, orelastomeric polyacrylates, or elastomeric olefins such asethylene-propylene rubbers, or elastomeric silicones andfluorosilicones, or elastomeric polyurethanes. In general the less gaspermeable, particularly less water vapor permeable elastomers, arepreferred.

Drug delivery devices including closed cell elastomeric pumps arepreferrably configured and arranged to continuously or semi-continuouslyadminister the drug into the patient's mouth at an average rate for adelivery period of not less than 4 hours and not more than 7 days at arate in the range of 80%-120% of the average rate.

During the delivery of the drug-including suspension at a constant ratethe gas-including elastomer expands such that it occupies most or all ofthe volume vacated by the already delivered suspension and there arelarge gas bubbles within the elastomer. In an exemplary method ofproduction and operation of a system delivering the drug at an aboutconstant rate, a closed-cell elastomer can be placed in a drug reservoirequipped with an closed outlet or outlets for drug delivery andoptionally equipped with a septum for filling the reservoir. The drugreservoir can have walls made of a material that does not substantiallydeform at the operating pressure in the reservoir, for example thedeformation of the wall under the applicable pressure changing thereservoir volume typically by less than 5%, for example by less than 1%.The drug containing suspension can be then injected through the septum,compressing the gas-containing closed cells of the rubber andpressurizing thereby the reservoir. Opening the outlet or outletsinitiates the flow of the drug-including suspension, e.g., into themouth. The about constant pressure in the reservoir during the deliveryof the drug can be controlled, for example, by the type of the closedcell rubber.

An advantage of elastomeric infusion pumps for use in the mouth is thatit is possible to temporarily stop the drug delivery from the device ifthe patient wishes to temporarily remove the drug delivery device fromthe mouth. This can be accomplished, for example, by blocking or closingthe flow restrictor, e.g., the orifice, the glass capillary, or thenarrow bore tubing.

To minimize the change in flow rate when the patient drinks a hotbeverage, it is preferred to utilize elastomeric materials whose forceis relatively independent of temperature in the range of 37° C.-55° C.For example, the force in a fresh reservoir may increase by less than30%, 20% or 10% when the temperature is raised from 37° C. to 55° C.

Spring Driven Pumps.

Positive-pressure spring-powered pumps are powered by energy stored in acompressed spring. In one embodiment, the spring is compressed duringthe reservoir filling process, as the volume of the solid or fluid inthe reservoir increases. In another embodiment, the spring is relaxedprior to use, for example during storage and shipping of the product,and the spring is compressed during the process of inserting the pumpcomponent into the re-usable oral appliance. In yet another embodiment,the spring is relaxed prior to use and the spring is compressed duringthe process of placing the oral appliance into the mouth.

A significant advantage of spring-driven pumps for use in the mouth isthat it is possible to temporarily stop the drug delivery from thedevice if the patient wishes to temporarily remove the drug deliverydevice from the mouth. This can be accomplished, for example, byretracting the spring, restricting the further expansion or contractionof the spring, or blocking or closing the flow restrictor, e.g., theglass capillary or narrow bore tubing.

The spring of the invention is preferably an about constant forcespring. To minimize the change in flow rate as the solid or fluid isdelivered, it is preferred to utilize a sufficiently long spring, or acoaxial coupled spring set, or a sufficiently high tension in the springsuch that the difference between the starting and ending force appliedby the spring is less than 30%, 20%, or 10% of the starting force.

To minimize the change in drug administration rate when the patientdrinks a hot beverage, it is preferred to utilize spring materials whoseforce is relatively independent of temperature in the range of 37-55° C.For example, the force in a fresh reservoir may increase by less than30%, 20% or 10% when the temperature is raised from about 37° C. toabout 55° C.

The springs of the invention may be any type of spring, includingtraditional metal springs or a compressible elastomer. For example, thecompressible elastomer may be a solid such as isoprene, or it maycontain closed gas cells (e.g., neoprene).

An example of a spring-driven, fully disposable, constant-ratemedication infusion pump with flow restrictor is the Valeritas V-goinsulin patch pump, described in U.S. Ser. No. 13/500,136, incorporatedherein by reference.

In embodiments in which the drug is delivered into the mouth via a tubeor channel, the oral liquid impermeable drug reservoir may be kept freeof oral liquids by using a tube or channel coated with a hydrophobic ornon-stick material (e.g. paraffin, PTFE or fluorinated polyether),and/or designed with a diameter that would require a sufficiently highpressure so as to not allow saliva to enter.

Another embodiment of a spring driven drug pump, illustrated in FIG. 6,includes the use of a spring motor to rotate two columnar or conicalshaped drums 29 that are attached to the oral liquid impermeable drugreservoir 3 containing a suspension. The drums 29 are constructed of ahydrophobic or non-stick material, and can be configured with a tighttolerance to prevent introduction of saliva into the reservoir. Therotation of these drums can draw the suspension from the drug reservoir3, through the drums 29, and into the mouth. The drums can be configuredsuch that a cutout 30 defines the dosage, and the frequency of rotationof the drums 30 defines the drug delivery rate. In another embodiment,the cutout 30 would not be present and the spacing between the drums 29along with the speed of rotation of the drums 29 would define the drugdelivery rate. In order to maintain constant feeding and eliminate thepotential for gaps of drug to the drums, a spring 31 and piston 32 areemployed within the housing 4.

In another embodiment of a compression spring-driven drug deliverydevice, FIG. 8 illustrates a compression-spring driven pump delivering adrug suspension. One or more constant force compression springs 31 areused to push a compression plate 39 toward an orifice 75. The drug iscontained in an oral liquid impermeable reservoir with rigid walls 4.For example, the rigid walls and compression plate may include a syringebarrel and a plunger which creates a seal that prevents leakage of thedrug into the compartment containing the spring. In order to eliminatethe effect of changes in ambient pressure on the drug delivery rate, avent hole 15 is present within the device to allow both the drugreservoir 3 and the drug reservoir nozzle 80 to be exposed to ambientpressure, which reduces or eliminates the effect of change in ambientair pressure (e.g., by the patient sucking on the device and/or changein altitude). The drug delivery device may optionally include a one-wayvalve 16.

As illustrated in FIG. 9, a particularly advantageous embodiment is theuse of two coaxial compression springs 31 and 19 connected via a coupler18 wherein, upon compression, a first spring with a first diameter iswholly or partially nested within a second spring with a second, largerdiameter. Such an embodiment provides for a smaller overall length and areduced variation in force across the stroke length, as compared to theuse of a single spring.

In a further embodiment of a coil spring-driven drug delivery device,FIGS. 7A and 7B illustrate an embodiment in which one or more constantforce springs are used to pull a compression plate toward an orifice. Aflexible and/or deformable oral liquid impermeable reservoir within ahousing contains the drug. The end of the spring rides along a track onthe inside of the housing. FIG. 7A, shows the location of the spring 37,spring axle 38 and compression plate 39 when the reservoir 3 is full andthe spring 37 is fully extended. FIG. 7B shows the location of thecompression plate 39 and spring 37 when the retraction of the spring 37has delivered all of the drug from the reservoir 3. In a relatedembodiment, the drug can be contained within the housing itself and thecompression plate would create a seal and act as a plunger to deliverthe drug in a manner similar to a syringe. In this embodiment, thespring rides inside of the housing and inside of the drug chamber,within a sealed sleeve, protecting the drug from exposure to the spring.In order to eliminate the effect of changes in ambient pressure on thedrug delivery rate, an optional vent hole 15 is present within thedevice to allow both the drug reservoir 3 and the drug reservoir nozzle8 to be exposed to ambient pressure, which reduces or eliminates theeffect of change in ambient air pressure (e.g., by the patient suckingon the device and/or change in altitude).

In another embodiment illustrated in FIGS. 7C and 7D, a constant forcespring 37 remains fixed in space; one end of the spring 37 is attachedto a compression plate 39, and pulls the compression plate 39 toward thedrug reservoir nozzle 8. FIG. 7C shows the location of the spring 37 andcompression plate 39 when the drug reservoir 3 is full and the spring 37is fully extended. FIG. 7D shows the location of the compression plate39 and spring 37 when the retraction of the spring 37 has delivered allor most of the drug from the reservoir 3. FIGS. 7C and 7D also have avent hole 15 incorporated into the design, to eliminate any effect ofambient pressure on the drug delivery rate.

In a further embodiment of a spring pump, one or more compressionsprings can be used to apply an approximately constant force to a pistonor plunger that applies that force to the drug reservoir. Using a verylong compression spring with a low spring rate, one could apply a forceacross a short stroke with relatively constant force. As an example, a10 inch long spring with a spring rate of 0.05 lbF/in would becompressed to 8.5 inch and would apply a force of 0.425 lbF. If thespring were allowed to expand to 7.5 inches (a 1 inch total stroke), theresulting force would be 0.375 lbF, which is a decrease of 12.5%throughout the stroke. In preferred embodiments, the spring force is inthe range of 0.25-10 lbF and is preferably less than 10 lbF, 5 lbF, or 1lbF; the spring rate is in the range of 0.01-1 lbF/inch and ispreferably less than 1 lbF/inch, 0.5 lbF/inch, or 0.05 lbF/inch; thestroke length is in the range of 0.5-1 inch and is preferably less than2 inches, 1 inch, or 0.5 inches; and the difference between the startingand ending force across the stroke is less than 15%, 10%, or 5%.

Pneumatic Pumps.

Pneumatic pumps generate a driving force using a pressure head of air.In one embodiment, a diaphragm pump generates a pressure head thatpushes a discreet amount of drug, in solid form (e.g., particles,granules or powder), from a reservoir and into the mouth. An example ofsuch a design, illustrated in FIG. 10, is a rotating disk 54 thatcontains compartments filled with suspension 55 that is injected by anair pressure bolus 57 at a pre-determined rate through an orifice 56that is fixed in place with respect to the rotating disk 54. Therotation of the disk 54 exposes a single compartment and the bolus ofair 57 delivers the drug from that compartment to the mouth at aspecific rate. The housing can be formed from a clear material thatwould allow the user to observe how much drug remains in the device. Inanother embodiment, the disk can contain a single compartment thatrotates and alternately fills the compartment from the reservoir anddelivers the drug with a bolus of air. In this configuration, the airnot only delivers the drug material, but also removes any saliva priorto re-filling the compartment from the reservoir.

Negative Pressure Pumps.

Negative-pressure pumps generate a driving force from the pressuredifference across two sides of the pump's low-pressure chamber wall,with one side being at low pressure (e.g., inside a partial vacuumchamber) and another side being at atmospheric pressure. The lowpressure in the vacuum chamber may be created during the reservoirfilling process. Expansion of the oral liquid impermeable reservoir,e.g., upon adding the drug-containing fluid to the reservoir, causessimultaneous expansion of the reduced pressure chamber, thus creating asignificant vacuum. During administration of the solid or fluid drug,pressure on the movable wall plunger is generated by the large pressuredifference between its two sides, causing it to move and compress thesolid or fluid in the drug-containing chamber.

A significant advantage of negative pressure pumps for use in the mouthis that it is possible to temporarily stop the drug delivery from thedevice if the patient wishes to temporarily remove the drug deliverydevice from the mouth. This can be accomplished, for example, byblocking or closing the flow restrictor, e.g., the glass capillary ornarrow bore tubing.

Gas-Driven Infusion Pumps.

In one embodiment, a gas-driven drug delivery device includes two ormore compartments, with pressurized gas in at least one compartment andthe suspension to be administered in at least one separate oral liquidimpermeable drug reservoir. The pressurized gas provides the drivingforce. The two compartments are separated by a movable member (such as aflexible and/or deformable diaphragm) that transmits the force from thegas compartment to the suspension.

The housing containing the two compartments is typically constructed tohave a fixed volume that does not vary significantly as the drug isdispensed and the internal pressure declines in the compartmentcontaining the pressurized gas. An example is a reservoir in the shapeof a syringe barrel including: a fluid dispensing orifice at the distalend of the syringe barrel; a sealed proximal end of the syringe barrel;a mobile rubber or elastomeric plunger in the syringe barrel, whichseparates the syringe barrel into two compartments; a drug-includingfluid located in the distal compartment; and a pressurized gas in theproximal compartment. In another example, the drug compartment may havea bellows shape and may be surrounded by the gas compartment, such thatthe pressurized gas compresses the bellows and forces the drug-includingfluid through a flow restrictor.

FIGS. 11A, 11B, and 11C illustrate another embodiment, wherein a firstelastomeric drug reservoir 3 is compressed by a second elastomericcompartment 7 containing gas or propellant. In FIG. 11A, the drugdelivery device includes a housing containing a first, full elastomericdrug reservoir 3; a second empty, elastomeric compartment 7; and anoptional gas pump 11 and electronics. In one embodiment air and/orsaliva is pumped by the electronic (e.g., piezoelectric) pump 11 intothe second elastomeric reservoir 7. In another embodiment the secondelastomeric reservoir 7 contains a compressed gas or propellant, and nopump is required. In either embodiment, the pressure from the secondelastomeric reservoir 7 compresses the first elastomeric reservoircontaining the drug 3, forcing the drug out of the reservoir through aflow restrictor 58 at a constant rate. FIG. 11B illustrates the systemwhen the drug reservoir 3 is half-full. FIG. 11C illustrates the systemwhen the drug reservoir 3 is close to empty.

In one embodiment, a gas (e.g., carbon dioxide, nitrogen) is containedin a miniature gas cartridge or cylinder. The gas cartridges have anexternal volume of less than or equal to 5 mL, 2 mL, or 1 mL and havestored pressures of 100-500 psi, 500-1,000 psi, 1,000-4,000 psi, orgreater than 4,000 psi. Exemplary gas cartridges are product numbers40106 (1.00″ CO₂ Filled; 0.75 grams) and 40106IIN21750 Nitrogen cylinder(1.00″ N₂ Filled; 0.135 grams) manufactured by Leland Gas Technologies(2614 South Clinton Ave, South Plainfield, N.J. 07080) and productnumber SM-2 ( 5/32″ Single Acting, Spring Return, Sub-MiniatureCylinder) manufactured by Clippard Instrument Laboratory, Inc. (7390Colerain Avenue, Cincinnati, Ohio 45239). The gas from the miniaturecartridge or cylinder can be used to compress the oral liquidimpermeable drug reservoir, thereby delivering the drug. Thegas-pressurized cartridge can be used in conjunction with a one ortwo-stage regulator in order to provide a constant pressure gas flow asthe drug reservoir is emptied. FIG. 12 shows a schematic diagram of acommercially available two-stage regulator. Examples of miniaturetwo-stage regulators are the product categories PRD2 and PRD3manufactured by Beswick Engineering Co, Inc. (284 Ocean Rd, Greenland,N.H. 03840-2442). A two-stage regulator is used to gradually reduce thepressure from high to very low, in this example from the cartridge tothe piston chamber of the pump. The first stage 59 reduces the gaspressure to an intermediate pressure. The gas at that intermediatepressure then enters the second stage 60 and is further reduced by thesecond stage 60 to the working pressure. In a related embodiment, a gascartridge contains an optionally reversibly CO₂-absorbing or adsorbingsolid that maintains, e.g. in its Henry region, an about constant CO₂pressure at about 37° C. The reversibly CO₂-absorbing or adsorbing solidcan be, for example, a high specific surface activated carbon, silica,e.g., silica gel, modified with n-propylamine or with another amine orheterocyclic nitrogen compound. The BET (Brunauer-Emmett-Teller)specific surface of the materials can be greater than 50 m²/g such as,between 50 m²/g and 500 m²/g, or greater than 500 m²/g. The materialscan contain more than 0.5 millimoles of amine functions per gram, forexample between 1-5 millimoles of amine functions per gram. Exemplaryreversibly CO₂-absorbing or adsorbing solids are described, for example,by Z. Bacsik, N. Ahlsten, A. Ziadi, G. Zhao, A. E. Garcia-Bennett, B.Martin-Matute, and N. Hedin “Mechanisms and Kinetics for Sorption of CO₂on Bicontinuous Mesoporous Silica Modified with n-Propylamine” Langmuir2011, 27, 11118-11128 incorporated herein by reference and in thereferences cited by Bacsik et al, also incorporated herein by reference.The materials may also be in the MIL-53 family of soft porous crystals,such as MIL-53(AI), MIL-53(AI)-11.1% NH2, MIL-53(AI)-20% NH₂,MIL-53(AI)-50% NH₂, MIL-53(AI)-66.7% NH₂, and MIL-53(AI)-NH₂, asdescribed by M. Pera-Titus, T. Lescouet, S. Aguado, and D. Farrusseng“Quantitative Characterization of Breathing upon Adsorption for a Seriesof Amino-Functionalized MIL-53” (J. Phys. Chem. C 2012, 116, 9507-9516).In general, the reversibly CO₂ absorbing amine-modified carbon, zeolite,silica or silica gel adsorbs CO₂ when the silica also contains boundwater. The materials may also include high surface area carbon oractivated carbon as described for example in “Fixed bed adsorption ofCO2/H2 mixtures on activated carbon: experiments and modeling” by N.Casas, J. Schell, R. Pini, M. Mazzotti Adsorption (2012) 18:143-161 and“Pure and binary adsorption of CO₂, H₂, and N₂ on activated carbon” by JSchell, N Casas, R Pini, M Mazzotti in Adsorption (2012) 18:49-65.

The materials may provide an about constant CO₂ pressure of greater than1 bar, for example between 1.2 and 2.0 bar, or between 2.0 and 5.0 bar,or between 5 bar and 20 bar.

In yet another related embodiment the gas cartridge may contain a solidmetal hydride, providing at about 3° C. an about constant hydrogenpressure. The metal hydride may include an alloy, for example of a rareearth like lanthanum, and a transition metal like nickel, and may alsoinclude magnesium.

In some embodiments, the pressurized gas material remains in the gaseousstate through the temperature range of 0° C.-37° C. A disadvantage ofsuch embodiments is that the drug infusion rate tends to decline as thedrug is dispensed because the gas pressure declines as the gas expands.For this reason, it is preferred to utilize sufficiently high gaspressures in the pump such that the difference between the starting andending gas pressure is less than 30%, 20%, or 10% of the starting gaspressure.

To minimize the change in flow rate when the patient drinks a hotbeverage, it is preferred to minimize the volume of the gas relative tothe volume of the drug-including fluid. The volume of the gas can beless than 40%, 30%, 20% or 10% of the volume of the drug-including fluidin a fresh reservoir. For example, the force in a fresh reservoir mayincrease by less than 30%, 20% or 10% when the temperature is raisedfrom 37 to 55° C.

In a preferred embodiment, the drug delivery device includes a volatilepropellant in one compartment and the drug in a second compartment, thepropellant boiling at sea level atmospheric pressure at a temperatureless than about 37° C. The propellant is under greater than 1 barpressure, such that part or most of it is liquid at 37° C. and itsvolume is small. Optionally, the partly or mostly liquid propellant inthe device has at about 37° C. a saturated vapor pressure greater thanabout 1 bar and less than about 50 bar, for example greater than about1.5 bar and less than about 25 bar, such as greater than about 1.5 barand less than about 20 bar, such as greater than about 2 bar and lessthan about 15 bar, such as between 2 bar and 10 bar, such as between 3bar and 10 bar. In this embodiment, a propellant-driven drug deliverydevice can include an oral liquid impermeable drug reservoir with apressure-liquefied propellant, i.e., a propellant-containing compartmentwithin the drug delivery device, such that the pressurized, volatile,propellant liquid and the fluid including the infused drug reside in thedifferent compartments. Optionally, the wall material of thepropellant-containing compartment can be expandable or plasticallyeasily deformable, such as elastomeric or non-elastomeric, allowing forexpansion of the propellant-containing compartment as thedrug-containing fluid is depleted. Typically, some of the propellant isa gas at 1 bar pressure at 37° C. It can maintain an about constantpressure when the drug-including formulation is infused in the mouth. Inan embodiment shown in FIGS. 13A and 13B, the gas compartment isencapsulated by an expandable membrane 61 and resides within the oralliquid impermeable drug reservoir 3. The propellant exerts an aboutconstant pressure on the expandable membrane 61 as the expandablemembrane 61 expands and pushes the solid or fluid drug from the oralliquid impermeable drug reservoir 3 through a narrow-bore tubing 8.Optionally, a narrow bore tubing may serve as a flow restrictor tocontrol the delivery rate, or there may be a separate flow restrictor.FIG. 13A shows the compressed expandable compartment 61 containingpropellant within the full drug reservoir 3. FIG. 13B shows the nearlyempty drug reservoir 3 and the expanded expandable compartment 61containing propellant. The advantage of this embodiment is that the drugdelivery rate does not decline as the drug is dispensed.

In a preferred embodiment, the propellant and a solid or fluid drug arecontained within a rigid metal housing (e.g., titanium or titaniumalloy) that does not significantly deform under the pressure of thepropellant. The housing includes a liquid impermeable drug reservoir.The propellant and the drug are separated within the housing by aflexible and/or deformable diaphragm, which transmits the pressure fromthe propellant compartment to the drug compartment. The flexible and/ordeformable diaphragm may include a substantially pinhole free metalsheet, such as a tin-containing sheet or silver-containing sheet,typically of a thickness between 10 μm and 250 μm, e.g., between 20 μmand 125 μm, such as between 25 μm and 75 μm. To obtain a hermetic sealof the propellant compartment, the metal diaphragm may be welded to themetal housing, e.g by resistance welding (i.e., by application of anelectrical current pulse or pulse sequence).

In one embodiment, the gas can be contained in a gas-impermeable,non-flexible material, such as metallized Mylar®, which is folded suchthat the expansion of the gas unfolds the gas compartment and allows thepressurization of the solid or fluid drug to occur. Optionally, theunfolding compartment can be coil or bellows-like.

In another embodiment of a gas-driven pump, a propellant can be used todeliver a suspension containing a drug. In FIGS. 14A and 14B, thepropellant, contained within propellant chamber 63 pushes the piston 64which in turn applies a constant pressure to a column of the drugsuspension. The flow rate of the drug suspension 66 can be affected bythe friction at the interface of the suspension and the inner drugreservoir wall as well as by the check valve 65 located at the outletport. The resistance to flow can thus change as the drug reservoir 3 isemptied. To alleviate or eliminate this change, the resistance of theplunger movement, i.e. the friction, can be made sufficiently greaterthan the resistance of the suspension to maintain the flow rate withinthe desired tolerance. In a related embodiment, a vent within thehousing of a propellant driven piston allows the piston to be exposed toambient pressure, thereby eliminating the effect of changes in ambientpressure on the flow rate of the drug. This embodiment is illustrated inFIGS. 14C and 14D. FIG. 14C shows the drug reservoir 3 in its fullstate. The piston 64 is positioned against the drug reservoir 3 on oneend and within the propellant chamber 67 on its opposite end. The piston64 forms a seal with the propellant chamber 67 such that the propellantis allowed to pressurize and maintains its pressure within the volumecreated by the propellant chamber 67 and the piston 64. As thepropellant is exposed to body temperature, the propellant pressurizespushing the piston 64 against the drug reservoir 3. A vent 15 maintainsambient pressure around the drug reservoir 3. FIG. 14D shows the deviceafter some time has elapsed and the collapsible drug reservoir 3 hasemptied some of its contents. A filling septum 68 is located on theopposite end of the piston 64 allowing filling of the propellant chamber67.

In a further embodiment, the drug delivery device includes a propellantand a drug together in the same compartment. The saturated vaporpressure of the propellant at 37° C. can be between about 1 bar and 50bar, (e.g., 1.5-20 bar, 2-10 bar, or 1.5 and 6 bar). Part of thepropellant can be gas and part liquid at 37° C. at the pressure withinthe compartment. In this embodiment, a propellant-driven drug deliverydevice can include an oral liquid impermeable drug reservoir with apressure-liquefied propellant, i.e., volatile liquid propellant in thereservoir, such that both the pressurized, volatile, propellant liquidand the suspension including the infused drug reside in the samecompartment. The propellant may not be substantially dissolved in thedrug-containing composition, but could be dispersed in it to form anabout homogeneous mixture. The propellant can maintain an about constantpressure when the drug including formulation is infused in the mouth.

Because separation or segregation of the liquid propellant and the drugformulation could lead to oral delivery of propellant-enriched orpropellant-poor fluid and hence to lesser or greater than intended drugdosing, the liquid propellant can be dissolved or co-dispersed in thesuspension. The propellant liquid can be homogeneously dispersed in anyof the phases, for example in a non-aqueous phase, which may optionallybe part of an emulsion, formed optionally by adding an emulsifier, suchas a lecithin, or by Pickering emulsification, where small solid drug orother particles stabilize the emulsion. In general, the emulsions can bestable for at least 24 hours and can be re-formed by agitation, forexample by shaking. The optional emulsions can be foamable ornon-foamable and can include an emulsifier such as lecithin, a protein,or a surfactant that can be non-ionic, including for example a glycerylmonoester, like glyceryl monooleate, a Tween or a Polysorbate. Examplesof emulsifiers in propellant including mixtures are listed for examplein U.S. Pat. No. 6,511,655 and in U.S. Patent Publication No.2003/0049214, each of which is incorporated by reference.

Alternatively the liquid propellant can be dissolved in the carrierliquid of a solid drug including formulation, e.g. when the carrierliquid is non-aqueous, for example when it is edible oil or medicinalparaffin oil. The propellant dissolving carrier liquid may optionally bea temperature sensitive liquid such as cocoa butter.

As the drug is dispensed and the internal pressure falls in the gascompartment, volatile liquid propellant evaporates, thereby maintainingan about constant pressure within the oral liquid impermeable reservoir.The advantage of such an embodiment is that the drug infusion rate doesnot decline as the drug is dispensed.

In a related embodiment, a gas-driven drug delivery device includes anoral liquid impermeable drug reservoir having one or more compartments,with a non-toxic propellant gas (formed from the optionallysubstantially immiscible pressurized liquid when the pressure is reducedto about 1 bar) and the drug to be infused both present in at least onecompartment. The propellant gas provides the driving force. Thepressure-liquefied gas can optionally be insoluble in the fluidcontaining the drug, such that the pressure in the reservoir remainsabout constant at the about constant body temperature near 37° C. in themouth.

Alternatively, a pressurizing gas can be dissolved in the drug-includingfluid. For example, when the fluid infused in the mouth is aqueous, orwhen it includes ethanol, and the reservoir is pressurized, thepressurizing gas can be CO₂. When the fluid infused in the mouthincludes an edible oil such as a vegetable oil, a monoglyceride, adiglyceride or a triglyceride, or paraffin oil, and the reservoir ispressurized, the pressurizing gas can be a flurorohydrocarbon, a Freon™,or a saturated hydrocarbon or a non-saturated hydrocarbon such as anolefin. When the pressurizing gas dissolves in the fluid in the oralliquid impermeable reservoir the pressure can be about constant at theconstant about 37° C. temperature in the mouth, making the flow rateabout constant.

Examples of continuously subcutaneously drug infusing compressed air orFreon™ pressurized pumps include those described in U.S. Pat. Nos.4,265,241, 4,373,527, 4,781,688, 4,931,050, 4,978,338, 5,061,242,5,067,943, 5,176,641, 6,740,059, and 7,250,037, each of which isincorporated herein by reference. When the reservoir is refillable andwhen the pumping is by pressurization, the reservoir can be pressurizedupon its refilling.

An example of a propellant-driven, implanted medication infusion pump isthe Codman pump described in U.S. Pat. No. 7,905,878, European PatentNos. EP 2177792 B1 and EP 1527794 B1, each of which is incorporatedherein by reference.

To provide different patients with different dose rates, fluids withdifferent drug concentrations can be placed in the reservoirs, therebynot necessitating modifications to the drug delivery device or to theflow rate. Alternatively, the drug concentration in the reservoir can beheld constant and the flow rate can be changed, for example by changingthe diameter or length of the flow restrictor.

Exemplary volatile propellant compounds for use in the devices of theinvention include hydrocarbons (e.g., pentane; isopentane; 1-pentene;trans-2-pentene; trans-dimethylcyclopropane; ethylcyclopropane;1,4-pentadiene; 2-methyl-1,3-butadiene; and methyl-1-butane; 2-butyne);halocarbons (e.g., trichlorofluoromethane; difluoromethane;1,1-dichloro-1-fluoroethane; 2,2-dichloro-1,1,1-trifluoroethane;1-fluorobutane; 2-fluorobutane; perfluoropentane; 1,1-dichloroethylene;cis-1-chloropropene; and 2-chloropropene); esters (e.g., methylformate); ethers (e.g., diethyl ether), and hydrofluoroalkanes.Preferred propellants are those approved by the FDA for use inmedication inhalers, such as 1,1,1,2 tetrafluoroethane (sold as DuPont™Dymel® (r)134a/P); and 1,1,1,2,3,3,3 heptafluoropropane, sold as 227ea/P(sold as DuPont™ Dymel® 227ea/P). Also preferred are propellantsapproved by the FDA for topical applications, such as 1,1,1,3,3,3hexafluoropropane (sold as DuPont™ Dymel® 236fa); and propellantsapproved for use in food and over the counter anticarie drug products,such as octafluorocyclobutane and isopentane, respectively.

Exemplary pressurized liquid propellants and their vapor pressures at37° C. are listed in Table 1.

TABLE 1 Approximate Pressure, bars at Propellant 37° C. diethyl ether1.1 1-fluorobutane 1.3 isopentane 1.4 2-fluorobutane 1.61,2-difluoroethane 1.9 neopentane 2.4 methyl ethyl ether 3 2-butene 3.2butane 3.5 1-fluoropropane 4.1 1-butene 4.2 2-fluoropropane 51,1-difluoroethane 8.4 propane 12.8 propene 15.51,1,1,2-tetrafluoroethane 9.3 1,1,1,2,3,3,3-hepta-fluoropropane 6.41,1,1,3,3,3 hexafluoropropane 4.0 octafluorocyclobutane 4.3

When the pressurized gas and the drug are located in the samecompartment, the gas can be selected to be safe, non-toxic, andnon-irritating when delivered into the mouth and inhaled into the lungsat the delivery rates of the invention. Furthermore, the gas can beselected so as not to adversely affect the stability of the drug andformulation in the reservoir. Chemically inert gases, meaning gases thatdo not react at body temperature with any of the components of theorally infused composition, are therefore preferred. Preferably, thepropellant used in the drug delivery device of the invention isn-butane, isopentane, 1-butene, 1-fluoropropane, trifluorochloromethane,difluoromethane, dichlorofluoromethane,1,1,1,2,3,3,3-heptafluoropropane, 1,1,1,3,3,3-hexafluoropropane, or1,1,1,2-tetrafluoroethane.

A source of inaccuracy in propellant pressurized devices is that thepressure, such as the vapor pressure of a liquid propellant, increaseswith temperature. An important benefit of carrying within the mouth thedrug delivery devices of the invention is that the pressure is heldnearly constant at about 37° C., thereby minimizing variations in theinfusion rate.

In another embodiment, gas is generated by the gas-driven drug deliverydevice. For example, a low current electrolyzer may be used to generatehydrogen gas. Exemplary hydrogen gas generating systems are the hydrogengas generating cells sold by VARTA Microbattery GmbH Daimlerstr. 1,D-73479 Ellwangen/Jagst Germany. The VARTA systems are capable ofgenerating 130 ml, 260 ml or more ultrapure H₂ at high back pressure. Anadvantage of such a system is that gas need not be stored in the drugdelivery device prior to its use.

An advantage of gas-driven infusion pumps for use in the mouth is thatit is possible to temporarily stop, or greatly reduce, the drug deliveryfrom the device if the patient wishes to temporarily remove the drugdelivery device from the mouth. This can be accomplished, for example,by blocking or closing the flow restrictor, e.g., the orifice, the glasscapillary or the narrow bore tubing or by cooling to a temperature belowthat in the mouth, for example to the typically 20° C.-25° C. roomtemperature or by placing the device in a refrigerator typically at 3°C.-8° C.

Propellant-Driven Pumps

The following sections provide additional details on designs andmanufacturing processes of propellant-driven pumps for the delivery ofpharmaceutical compositions including LD/CD pastes. It will berecognized that similar designs and manufacturing processes may be usedwith other pumps and drug formulations of the invention.

The devices of the invention can be propellant-pumped, rigid walled,intraoral, continuously drug delivering devices having a drugcompartment and a propellant compartment separated by an optionallymetallic diaphragm. In one embodiment, the device for continuous orsemi-continuous intraoral drug administration is configured to beremovably inserted in a patient's mouth. The pump can bepropellant-driven. The drug delivery device includes a chambercontaining a propellant, a chamber containing a drug-including fluidsuch as a paste, and a flexible and/or deformable diaphragm separatingthe propellant chamber from the drug chamber. The housing of the devicecan be rigid and can be gas and liquid impermeable, for exampleimpermeable to gaseous and liquid propellant, gaseous nitrogen, gaseousor dissolved oxygen, gaseous or dissolved air, water vapor, liquidwater, saliva and/or gaseous helium; the drug reservoir can be an oralliquid impermeable reservoir. In a preferred embodiment, the rigidhousing forms a wall of a chamber containing the drug-including fluidand a wall of a chamber containing the propellant, and the two chambersare separated by a diaphragm. The separating diaphragm includes a metal,i.e., the diaphragm can be metallic or a metallized polymer. The devicedispenses at least 50% (e.g., 50%-99%, 60%-95%, 75%-95%, 51%-60%,61%-70%, 71%-80%, 81%-90%, 91%-95%, or 95%-99%) of the weight of thedrug-including fluid (e.g., paste) in the chamber, preferably while therate of drug delivery, meaning the flow rate or extrusion rate, variesby less than ±20% (e.g., less than ±15%, less than ±10%, or less than±5%) over a period of greater than or equal to 4, 8, 16, or 24 hours.

The rigid wall of the drug and the propellant including chambers (whichcan include part of the housing) can be strong, dense and it can bemetallic. In a preferred embodiment, the rigid housing forms a wall ofthe drug-containing chamber and/or a wall of the propellant-containingchamber. The rigid housing of the chamber wall can be strong andincludes a metal, ceramic, or a composite of a polymer reinforced byfibers. The fibers reinforcing the polymer can include, for example,carbon fibers, glass fibers, or metal fibers. The housing can include amaterial having at about 25±3° C. a tensile yield strength greater than100 MPa, such as greater than 200 MPa, 300 MPa, 400 MPa, or 500 MPa;and/or the housing can include a material having at 25±3° C. a modulusof elasticity (Young's modulus) greater than 30 GPa such as greater than50 GPa, 75 GPa, or 100 GPa; and/or the housing can include a materialhaving at 25±3° C. a Brinell hardness greater than 200 MPa, such asgreater than 400 MPa or 600 MPa; and/or the housing can include amaterial having at 25±3° C. a density greater than 2.5 g/cm³, such asgreater than 3.5 g/cm³, such as about equal to or greater than 4.5g/cm³, 5.5 g/cm³, 6.5 g/cm³, or 7.5 g/cm³. When metallic, the metal ofthe housing can be selected from the group titanium, iron, aluminum,molybdenum, or tungsten, or an alloy of titanium, iron, aluminum,molybdenum, or tungsten; it can include, for example, titanium or analloy of titanium.

The diaphragm separating the chamber containing the drug-including fluidfrom the chamber containing the propellant can be a flexible and/ordeformable metal foil or it includes a flexible and/or deformable metalfoil. In a preferred embodiment, the diaphragm separating the chambercontaining the drug-including fluid from the chamber containing thepropellant can be metallic or includes a metal. It can be a flexibleand/or deformable, pinhole-free metal foil. The density of the diaphragmmetal can be greater than 2.0 g per cm³ at 25° C. It can be for examplegreater than 2.5 g per cm³, such as greater than 4.0 g per cm³, 7.0 gper cm³, or 10.0 g per cm³ at 25° C. Optionally, the tensile strength ofthe diaphragm material can be greater than 25 MPa, for example it can begreater than 50 MPa, 75 MPa, or 100 MPa at 25±3° C. and/or its elasticmodulus can be greater than about 20 GPa, such as greater than 30 GPa,40 GPa, or 50 GPa. The metallic diaphragm can include, for example,silver or an alloy of silver; alternatively, it can include tin or analloy of tin; or it can include aluminum or an alloy of aluminum; or itcan include magnesium or an alloy of magnesium; or it can includetitanium or an alloy of titanium; or it can include copper or an alloyof copper. The diaphragm can be a pinhole-free flexible and/ordeformable foil of silver, tin, aluminum, magnesium or copper. Whenheated, the metallic diaphragm can optionally alloy the metal of thehousing, such that the diaphragm is welded at its rim to the housingwall to form a hermetic, gas-impermeable seal (e.g. impermeable topropellant and/or helium). The diaphragm can be shaped to substantiallyconform to the interior housing wall of the drug chamber, to theinterior housing wall of the propellant chamber, or to the interiorhousing walls of both chambers. As illustrated in FIGS. 23A-C, in apreferred embodiment the propellant-driven pump includes a drug chamber89 and a propellant chamber 93 separated by a diaphragm 90. Thediaphragm 90 is attached to the two housings by a weld 91. The pumpfurther includes a sealable port 92 for introduction of the propellant,e.g., via needle or nozzle injection. FIG. 23 A shows the initialconfiguration of the pump where the drug and propellant chambers arefull. FIG. 23 B shows the pump partially full and FIG. 23 C shows thepump upon completion of the delivery of the drug.

The housing can be made of two or more parts joined together. The partsmay be joined together by welding (optionally with a diaphragm) or byforming a compression seal (meaning a seal formed by pressing the partstogether), the parts optionally separated by sealant exemplified by apolymer or a soft metal like tin. The interior housing wall of thepropellant chamber and interior housing wall of drug chamber can besubstantially mirror images of each other, meaning that they can besubstantially symmetrical with respect to a central plane, exceptingthat their ports differ and an interior housing wall of the drug chambermay have grooves or similar flow-enhancing features while the mirroringinterior housing wall of the propellant chamber may not have grooves orsimilar flow-enhancing features.

In a preferred embodiment the housing wall of the drug chamber caninclude a sealable port that allows for the introduction of apharmaceutical composition. The port may be temporarily or permanentlysealed prior to or after the filling process, e.g., by a grommet,septum, drug delivery nozzle, flow restrictor, or delivery tube. Theport may optionally also be used for delivery of the drug duringoperation of the device, e.g., by attaching a drug delivery nozzle, flowrestrictor, or delivery tube. Optionally, the flow-controlling nozzles,channels or tubes can be made of a plastic, such as an engineeringplastic. The nozzles, channels or tubes can have an internal diameterless than 1 mm, 0.6 mm, 0.3 mm or 0.1 mm and they can be shorter than 10cm, 5 cm, 2 cm or 1 cm such as 0.5 cm. Preferred minimum internaldiameters are 0.1-2 mm (0.1-0.7 mm, 0.2-0.5 mm, 0.5-0.75 mm, 0.75-1.0mm, 1.0-1.5 mm, or 1.5-2.0 mm) and preferred lengths are 0.25-5 cm (suchas 1-2.5 cm, 1-5 cm, 0.25-0.5 cm, 0.5-0.75 cm, 0.75-1 cm, 1-2 cm, 2-3cm, 3-4 cm, or 4-5 cm).

FIG. 24 and FIG. 25 show a port 102 in a pump housing 101 forming a wallof a chamber 89 containing a pharmaceutical composition (e.g., a LD/CDsuspension) with an elastomeric grommet 94 inserted into the port. Afilling nozzle 95 may be inserted through the grommet to fill thedrug-containing chamber 89 with the pharmaceutical composition. Thefilling nozzle 95 may then be removed and replaced with the deliverynozzle 96.

Preferably, the housing wall of the propellant chamber includes asecond, sealable port (e.g., containing a grommet, septum, or similarresealable member) for filling the propellant chamber with propellant. Apropellant delivery nozzle can be inserted into the septum and thepropellant chamber is filled. Preferably, the drug chamber is filledfirst and the propellant chamber is subsequently filled.

Patient compliance depends on the drug delivery device and retainerbeing comfortable when worn in the mouth. Preferably, the system doesnot substantially affect the appearance of the wearer, impede speech, orimpede swallowing and drinking. For comfort and in order to avoidsubstantial change in the appearance of the face of the wearer the oralpump may have a substantially obround shape. An exemplary location ofthe pump in the mouth is a maxillary location. In general it ispreferred that the pump and/or its drug outlet be located such that thelikelihood of excessive drug accumulation in the buccal vestibule isavoided. In order to avoid irritation of tissue the surfaces of the pumpis smooth. For examples, pump surfaces contacting buccal tissue may haveprotrusions that are less than about 100 μm, e.g., less than about 30μm, 10 μm, 5 μm, or 1 μm.

The pump may contain between about 0.1 mL and about 2 mL of thedrug-including fluid, such as between about 0.2 mL and about 1.2 mL, forexample between about 0.6 mL and about 1 mL. An exemplary pump with a0.8 mL drug reservoir contains about 1 g of an about 1.25 g/mL densitycomposition. In some compositions, there can be 800 mg/mL of the mostlysolid containing composition, the solid being mostly the solid drugitself or mostly solid excipient. When the solid is a drug of about 1.5g/mL density such as LD or CD, the reservoir can contain about 0.64 g ofmostly solid drug.

The pump can be, for example, substantially obround shaped or it can besubstantially flattened teardrop shaped. The dimensions of thesubstantially obround-shaped pump are width, measured from thevestibular surface of the teeth outward, height measured in thedirection of tooth eruption, and length measured along the direction ofa series of teeth, typically including a molar. The width (outerdimension, OD) of the pump housing can be between about 3 mm and about10 mm; its height (OD) can be between about 5 mm and about 18 mm; itslength (OD) can be between about 10 mm and about 30 mm. Preferably, thelength of the pump housing can be such that the pump housing spans oneor two teeth, but not three teeth. The thickness of the wall of thehousing can be between about 0.2 mm and about 2 mm, such as betweenabout 0.3 mm and about 1.0 mm.

The width of the substantially flattened teardrop shaped pump, itslength and the thickness of the housing of the wall can be similar tothose of the obround pump. The height of its anterior side when residingin the buccal vestibule can be less than the height of its posteriorside. The posterior side can be, for examples, between 1.1 times andtwice as high as the anterior side, such as between 1.3 times and 1.8times as high, e.g., between 1.4 and 1.6 times as high.

In one embodiment the metallic diaphragm is about uniformly thick and itis free of pinholes. The thickness of the pinhole-free metallicdiaphragm can be between about 10 μm and about 1 mm. The diaphragm canbe, for example, between about 10 μm and 250 μm, e.g., between 20 μm and125 μm, such as between 25 μm and 75 μm. The thickness and theassociated rigidity of the diaphragm, meaning its resistance to changeof shape under stress, can vary by less than ±25% across the diaphragm,such as by less than ±10%. In some embodiments the rim of the diaphragmis thicker than the about uniformly thick center in order to facilitatesealing, e.g., creation of a hermetic seal via welding. The aboutuniformly thick center can constitute about 80% or more of the area ofthe diaphragm, the thicker rim constituting typically less than about20% of the area of the diaphragm. The rim of the diaphragm can be morethan 1.5 times as thick as its center, e.g., 1.5-2 times as thick as thecenter, or 2-3 times as thick, or more than 3 times thicker than thecenter. In another embodiment, the diaphragm has a non-uniform thicknessalong its length and/or width. This variable thickness allows thediaphragm to counteract internal forces and deflect in a predictablemanner.

The peripheral rim of the diaphragm is shaped and sized to match theperipheral rim of the central cross sectional plane of the typicallyobround or flattened teardrop shaped housing. The diaphragm can be made,for example, by forcing a sheet of metal, such as annealed about puresilver foil or tin foil of a thickness between 0.02 mm and 0.10 mm intoa mold. Alternatively, the diaphragm can be made by stamping a formablemetal foil or sheet, typically of a thickness between 0.02 mm and 0.10mm. Parameters that can affect formability include the strain, orwork-hardening, exponent of the metal (termed its n-value) and thestrain ratio in the width and thickness directions (termed its r-value).Typical r-values of the silver of which the diaphragms are made are from0.75 to 1.0 and typical n-values are from 0.2 to 0.4. The height of thestamped, metallic, optionally obround, cup-shaped diaphragm (matchingabout the width of the housing) can be between about 3 mm and about 10mm; its width (matching the height of the housing) can be between about5 mm and about 18 mm; and its length can be between about 10 mm andabout 30 mm. The optionally obround diaphragm may be folded, pleated, orscored. It can be formed, for example, by hydroforming or by stamping,optionally with heating by hot-stamping. It can be formed by stamping ordeep drawing, optionally with heating, or it can be formed byelectroplating or by electroless plating.

Optionally, the flexible and/or deformable metallic diaphragm separatingthe drug and propellant chambers can be welded to the housing to formhermetically sealed chambers with propellant filling and drug deliveryports. The pump can be hermetically sealed, meaning that its drugincluding chamber and its propellant including chamber are hermeticallysealed, except for the one, two or more drug delivery ports from thedrug chamber. Each of the chambers can include one or more ports forfilling and for release of gas, such as air or nitrogen or any inert gaspresent in the chamber while it is being filled. The housing wall of thedrug including chamber can include one, two, or more hermeticallysealable or sealed ports for filling with drug and/or for drug delivery.The ports are hermetically sealable or sealed after filling.

The housing wall of the drug including chamber can include one or moresealable or sealed ports for drug delivery. The propellant containingchamber can be hermetically sealed and can include a hermeticallysealable or sealed port for filling with propellant.

When stored, the pump can be hermetically sealed. When in use, the drugcan flow or be extruded through the one, two, or more drug deliveryports, to which a flow controlling tubing or pipe can be attached orwhich can itself control the flow.

As shown in FIGS. 23A-C, for hermetic enclosure the drug chamber 89,propellant chamber 93, and diaphragm 90 are joined by a hermeticallysealing weld 91, the hermetically sealing weld 91 preventing, forexample, the influx of air or water vapor, or the out-flux of optionallyinert gas (e.g., nitrogen or argon), or of water vapor, or of saliva, orthe out-flux of any constituent of the drug including composition fromthe drug chamber, or the out-flux of propellant from the propellantchamber during the rated shelf-life of the device, which can be longerthan 3 months, such as longer than 6, 12, 18, or 24 months. Optionally,the weld can prevent the influx of helium into and/or out-flux of heliumfrom the drug-including chamber, and/or from the propellant-includingchamber, or from both chambers. The hermetically sealing weld can be aweld between a metallic housing and a metallic diaphragm, where themetals of the housing and the diaphragm are the same or they can differ.The weld can be, for example between a metal forming a wall of thehousing, meaning the wall of a drug-including and/or apropellant-including chamber, and a different metal of the diaphragm,typically melting at a lower temperature than the metal of the housing.For example, the housing can include titanium or an alloy of titanium towhich a metallic diaphragm is welded. The diaphragm welded to thetitanium or titanium alloy housing can include, for example, silver oran alloy of silver. The hermetically sealing weld can include an alloyof silver and titanium. Alternatively, the housing can include iron oran iron alloy, such as steel exemplified by a stainless steel, and thediaphragm can include silver or a silver alloy or tin. The hermeticallysealing weld can be between a metallic diaphragm that can be welded toiron or an alloy of iron. The weld can include, for example, an alloyincluding silver and iron or silver and nickel. The method of formingthe hermetic weld can include, for example, resistance welding, laserwelding or electron beam welding. The method of welding can includeadditional steps like pre-heating, i.e., heating the diaphragm and thehousing prior to their welding, and/or annealing after welding,optionally at a temperature between 400° C. and 700° C. typically for 15min or more.

The devices of the invention can include channels, grooves, or tubesproviding constant rate delivery of most or nearly all of the drug.During the delivery of the drug the diaphragm may deform such that itpartially or completely isolates a volume of the drug-including fluidwithin the drug-containing chamber from the outlet port or ports. Suchisolation can result in stoppage of drug flow or reduction in the flowrate of the drug including fluid while the chamber still contains asubstantial fraction of the fluid. In order to deliver at an aboutconstant rate most or nearly all of the drug including fluid in thechamber, the device can include channels that reduce or eliminateblockage by the diaphragm when it extends into the drug-includingchamber during the delivery. Exemplary blockage reducing or preventingchannels are tubes inserted in the drug including chamber and connectedto one outlet port or several outlet ports in the chamber; or agroove-including insert in the chamber; or a groove or grooves in a wallof the chamber. For example, a grooved plate or a tube can be insertedin the drug including chamber to form a channel or multiple channels inwhich the drug can flow. The tube, tubes, groove or grooves can form achannel or multiple channels that remain open and unblocked by thediaphragm after more than 50% (such as more than 60%, 70%, 75%, 80%,85%, 90%, or 95%) of the weight of the drug in the chamber can bedelivered. Optionally, there are multiple grooves forming multiple flowchannels that are optionally interconnected, the interconnectionsallowing flow between the channels. FIGS. 26A and 26B show exemplarygrooves in surfaces of the drug including chamber. In one embodimentillustrated in FIG. 26A, the grooved flow channels 97 cause flow fromindividual locations within the pump to channel to the nozzle 98. Inanother embodiment illustrated in FIG. 26B, the interconnected flowchannels 99 form a network of channels that feed into a single centralchannel 100 in the housing wall 101.

The groove or grooves are typically 1 mm to 20 mm long, 0.5 mm to 3 mmwide, and 0.5 mm to 3 mm deep. The tube or tubes are typically 1 mm to20 mm long, 0.5 mm to 3 mm wide, and of 0.5 mm to 3 mm diameter. Thenumber of optionally interconnected flow channels 99 formed by thegrooves is typically between 1 and 10. Typically at least onegroove-associated flow channel remains open after the diaphragm has beenfully extended into the drug chamber at or near the exhaustion of thedrug contained in the chamber.

In a preferred embodiment, greater than 60% (e.g., 75%-85%, 86%-95%, orgreater than 95%) of the drug-including fluid can be dispensed while thedelivery rate varies by less than ±20% (e.g., less than ±15%, ±10%, or±5%) over a period of greater than or equal to 4 hours (e.g., greaterthan or equal to 8, 16, or 24 hours).

In a related embodiment, the flexible and/or deformable diaphragm may beshaped and sized such that it contacts only a limited portion (or evennone) of the interior wall surface of the drug chamber (excluding thesurface area of the diaphragm itself) as the drug chamber approachesexhaustion. For example, the diaphragm may be shaped and sized so thatit contacts 0%-10%, 11%-20%, 21%-30%, 31%-40%, or 41%-50% of theinterior surface area of the drug chamber (excluding the surface area ofthe diaphragm itself) after delivery of 85%, 90%, or 95% of the startingdrug product in the drug chamber. The interior surface of the drugchamber may include, for example, an interior wall of the pump housing.In a particular embodiment, the flexible and/or deformable diaphragm maybe shaped and sized such that it does not contact the drug exit orificefrom the drug chamber after delivery of 85%, 90%, or 95% of the startingdrug product in the drug chamber.

Typically, neither the metal of the rigid housing nor of the diaphragmmay corrode visibly after 3 months when the housing metal and thediaphragm metal are electrically shorted and are immersed in asubstantially de-oxygenated 0.1 M citrate buffer solution of about pH 4at about 23±3° C. The de-oxygenated solution can be a solution keptunder nitrogen. Typically, neither the metal of the rigid housing nor ofthe diaphragm may corrode visibly after 3 months while the housing metaland the diaphragm metal are electrically shorted and are immersed in anair-exposed 0.1 M citrate buffer solution of about pH 4.0 at about 23±3°C. The density of the current flowing between two electrically shortedelectrodes of about equal area, one of the metal of the rigid housing,the other of the metal of the diaphragm, can less than 2 μA cm⁻² such asless than 0.5 μA cm⁻², for example less than 0.1 μA cm⁻² when theelectrodes are immersed in a substantially de-oxygenated about pH 4 0.1M citrate buffer solution at 23±3° C. for 24 hours or more.

In order to obtain the desired rate of delivery of the pharmaceuticalcomposition without clogging the flow restrictor (e.g., the nozzle) theapparent viscosity and the particle size of the pharmaceuticalcomposition, the vapor pressure, as well as the diameter and length ofthe flow restrictor are simultaneously controlled. Table D providesexemplary ranges for these simultaneously controlled parameters for anintra-oral drug delivery device and formulation of the invention.

TABLE D Exemplary parameter ranges for continuous intra-oral drugdelivery devices and formulations Propellant Drug or Drug or ViscosityFlow Vapor Oral Excipient Excipient at about Flow Restrictor Pressure,Extrusion Particle Particle 37° C., Restrictor Length, bar at aboutRate, Size, D₉₀, Size, D₅₀, Poise ID, mm cm 37° C. mL/hour μm* μm**Possible 100- 0.05-3.00 0.25-20   1.2-50  0.001-1.000  0.1-200  0.1-50 500,000 Typical 200- 0.1-0.7 1.0-5.0  2.5-15.0 0.03-0.5  1.0-50  0.5-30 100,000   Preferred 500- 0.2-0.5 1.00-2.5   4.0-10.0 0.05-0.2  3.0-30 2.00-20.0  75,000 *Measured by light scattering when the particles aresuspended in a non-solvent, e.g. with a Malvern Ltd (UK) Mastersizer.**Typically the viscous compositions contain drug particles and/orexcipient particles and can be pastes; they can, however, also be gelsor true solutions, e.g., thickened (made viscous by a dissolvedmacromolecule) particularly when the drug concentration is low and/orthe drug is highly soluble (its concentration being, e.g., between 0.001mg/mL and 500 mg/mL).

The oral device can continuously or semi-continuously extrude or infusea viscous drug-containing composition into the mouth; it can alsoinclude a mechanical pump comprising, for example, a spring, pressurizedgas, or propellant. The device can include a flow restrictor such as anozzle, a channel, a tube or any other flow or extrusion restrictingcomponent. The extrusion or flow rate through the nozzle can depend onits internal diameter, on its length, and on the vapor pressure of theliquid propellant.

The oral device can include a viscous drug-containing paste, or aviscous orally infused drug-containing solution, or a viscousorally-infused drug containing suspension extruded or infused into themouth at a rate that can be between 0.001 mL/hour and 1.25 mL/hour(e.g., 0.015-1.25 mL/hour). The viscosity of the paste, the solution orthe suspension can be greater than 100 poise and less than 500,000 poiseat about 37° C.; its extrusion rate or flow restrictor (e.g., nozzle)can have an internal diameter between 0.05 mm and 3.00 mm and a lengthbetween 0.25 cm and 20 cm (e.g., 0.5-4 cm); the device can include apropellant having a vapor pressure at about 37° C. greater than 1.2 barand less than 50 bar (e.g., 1.5-10 bar). When a paste including drugparticles and/or excipient particles is extruded into the mouth, theparticle size distribution, measured by light scattering (e.g. with aMalvern Mastersizer after dispersing the paste in a liquid non-solvent)can have a D₉₀ between 0.1 μm and 200 μm and a D₅₀ between 0.1 μm and 50μm.

A typical device can include a viscous drug-containing paste, or aviscous orally infused drug-containing solution, or a viscousorally-infused drug-containing suspension, extruded or infused into themouth at a rate that can be between 0.03 mL/hour and 0.5 mL/hour. Thetypical viscosity of the paste, solution or suspension can be greaterthan 200 poise and less than 100,000 poise at about 37° C.; itsextrusion rate or flow rate can be controlled mostly by a flowrestrictor (e.g., nozzle) which can have an internal diameter between0.1 mm and 0.7 mm and can be between 1 cm and 5 cm long; the typicaldevice can also include a mechanical pump. The mechanical pump caninclude a propellant having a vapor pressure at about 37° C. that can begreater than 2.5 bar and can be less than 15 bar. When a paste includingdrug particles and/or excipient particles is extruded into the mouth,the particle size distribution measured by light scattering (e.g., witha Malvern Mastersizer after dispersing the paste in a liquidnon-solvent) can have a D₉₀ between 1 μm and 50 μm and a D₅₀ between 0.5μm and 30 μm.

In a preferred embodiment the device can include a viscousdrug-containing paste, or a viscous orally infused drug-containingsolution, or a viscous orally-infused drug containing suspension,extruded or infused into the mouth at a rate 0.05 mL/hour and 0.2mL/hour. The paste, or the solution, or the suspension can have aviscosity greater than 500 poise and less than 75,000 poise; itsextrusion rate or flow rate can be controlled mostly by a flowrestrictor (e.g., nozzle), which can have an internal diameter between0.2 mm and 0.5 mm and a length between 1 cm and 2.5 cm; the device canalso include a propellant having a vapor pressure at about 37° C. thatcan be greater than 4 bar and can be less than 10 bar. When a pasteincluding drug particles and/or excipient particles is extruded into themouth, the particle size distribution measured by dispersing theparticles in a liquid non-solvent by light scattering (e.g., with aMalvern Mastersizer after dispersing the paste in a liquid non-solvent)can have a D₉₀ between 3 μm and 30 μm and a D₅₀ between 2 μm and 20 μm.

Also disclosed is the method of continuously or semi-continuously orallyextruding or infusing a viscous drug-containing paste, or for infusing aviscous drug-containing solution, or a viscous drug-containingsuspension, at an extrusion rate or flow rate between 0.001 mL/hour and1.25 mL/hour; the paste, solution or suspension can have a viscositygreater than 100 poise and less than 500,000 poise; the extrusion rateor the flow rate can be controlled mostly by a flow restrictor (e.g.,nozzle) having an internal diameter between 0.05 mm and 3.00 mm and alength between 0.25 cm and 20 cm; the extrusion or infusion can bedriven by a mechanical pump. The mechanical pump can include apropellant, the propellant can have a vapor pressure at about 37° C.greater than 1.2 bar and less than 50 bar. The paste or the suspensionor the solution can include solid drug and/or excipient particles whoseparticle size distribution (when dispersed in a non-solvent and whenmeasured by light scattering) can have a D₉₀ between 0.1 μm and 200 μmand a D₅₀ between 0.1 μm and 50 μm.

In a typical method of oral extrusion or infusion the extrusion or flowrate can be greater than 0.03 mL/hour and less than 0.5 mL/hour and thetypical paste, suspension or solution can have a viscosity greater than200 poise and less than 100,000 poise; the typical flow restrictor(e.g., nozzle) can have an internal diameter can be between 0.1 mm and0.7 mm and the typical nozzle length can be between 1 cm and 5 cm; atypical propellant can have a vapor pressure at about 37° C. greaterthan 2.5 bar and less than 15 bar. The typical paste or the suspensionor the solution can include solid drug and/or excipient particles whoseparticle size distribution (when dispersed in a non-solvent and whenmeasured by light scattering) can have a D₉₀ between 1 μm and 50 μm anda D₅₀ between 0.5 μm and 30 μm.

In a preferred method of oral extrusion or infusion the flow rate can begreater than 0.05 mL/hour and less than 0.2 mL/hour; the preferredpaste, suspension or solution can have a viscosity greater than 500poise and less than 75,000 poise; a preferred flow restrictor (e.g.,nozzle) can have an internal diameter between 0.2 mm and 0.5 mm and alength between 1 cm and 2.5 cm; and a preferred propellant can have avapor pressure at about 37° C. greater than 4 bar and less than 10 bar.The preferred paste or suspension can include solid drug and/orexcipient particles whose particle size distribution (when dispersed ina non-solvent and when measured by light scattering) can have a D₉₀between 3 μm and 30 μm and a D₅₀ between 2 μm and 20 μm.

Ambient-Pressure and Suction Independent Pump Designs

The invention includes intra-oral drug delivery devices whose rates ofdrug delivery are substantially independent of increases or decreases inambient pressure in the mouth and/or in the atmosphere, e.g., devicesthat do not deliver clinically significant, undesired boluses as theambient pressure changes. A source of inaccuracy in many device designs,including many pumps pressurized by a spring, a propellant or bycompressed gas can be that the rate of drug delivery can vary as (a) theambient air pressure changes, e.g., at sea level (14.7 psia or 1 bar)versus at 7,000 feet elevation or in an airplane (both about 11.3 psiaor 0.78 bar), and (b) the patient sucks on the drug delivery device. Theinvention includes pressure-invariant pumps whose drug delivery rate canbe substantially insensitive to changes in atmospheric pressure. Theinvention also includes suction-induced flow limiters that substantiallyreduce or eliminate the delivery of a drug bolus when a patient sucks onthe drug delivery device.

In some embodiments, the spring or propellant compartment ishermetically sealed so that the components are not exposed to saliva,food, liquids, and potentially deleterious conditions (e.g., acids,bases, alcohols, oils, and solvents in the mouth). In preferredembodiments, drug delivery devices of the invention include spring orpropellant-pressurized surfaces in the spring or propellant compartmentsthat are in fluidic (gas and/or liquid) contact with the ambientatmosphere via one or more ports or openings in the housing of the drugdelivery device. Preferred designs for ambient pressure independentspring-driven and propellant-driven pumps are those in which both thedrug outlet and the spring or propellant-pressurized surface (e.g., apressure plate or plunger) are exposed to the ambient pressure, i.e.,the pressurized surface is not enclosed within a hermetically sealedchamber. With such a design, changes in ambient pressure are the same atthe drug outlet and at the pressurized surface, resulting in no changeto the rate of drug delivery.

In another embodiment, the system can be designed to keep the change inthe rate of drug delivery within a desired limit by using a sufficientlyhigh pressure inside the device. For example, for the flow rate to varyby less than about 10% across the range of about 1.013 to about 0.782bar pressure (sea level to about 7,000 feet) the system can becalibrated such that it delivers drug at its target rate at the pressuremidpoint, i.e., about 0.898 bar. Then, for a 0.116 bar ambient pressurechange to cause less than a 10% change in the rate of drug delivery itis necessary for the drug delivery device to have an internal pressureof greater than about 1.00+(0.116/0.1)=2.16 bar. In such a manner it ispossible to achieve any desired accuracy across a specified ambientpressure change. For example, to achieve accuracies within ±20%, ±15%,±10%, ±5%, or ±3% across the ambient pressure range of 1.013 to 0.782bar requires propellant pressures of about 1.58, 1.77, 2.16, 3.31, and4.85 bar, respectively. Preferred spring-driven, gas-driven, orpropellant-driven drug delivery devices of the invention maintain aninternal pressure of greater than or equal to about 1.5, 1.75, 2, 3, 4,or 5 bar.

A low pressure condition can be created within the mouth if the patientsucks air out of the mouth or sucks directly on the drug deliverydevice. Humans are able to draw a negative pressure of up to about 0.14bar in the mouth. The lowered pressure can cause a drug bolus to bedelivered from the drug reservoir into the mouth. In some embodiments, ameans is provided for preventing premature evacuation of the drug fromthe drug reservoir under the suction conditions created within themouth. One example of such means is a fluidic channel designed such thatwhen the drug is being infused via a pressure head the fluidic channelinflates, and when the pressure in the mouth is low the fluidic channelcollapses, the collapse causing it to kink and temporarily halting theinfusion of the drug. In another embodiment, low ambient pressure in themouth causes a diaphragm to deflect and block the drug flow channel,examples of which can be seen in FIGS. 15A and 15B. FIG. 15A shows drugdelivery during normal operation. Drug from the drug reservoir 3 ispushed through the orifice 75 in the diaphragm 76 and into a chamber 77prior to entering the nozzle tube 78 and then out the nozzle withone-way valve 16. In FIG. 15B, an external vacuum is applied to theenvironment that the device occupies. This causes the diaphragm 76 to bedisplaced, blocking the orifice 75 from flow and halting flow throughthe nozzle 78. Another example of a means of addressing the issue ofbolus delivery of the drug due to low pressure in the mouth is the useof an inline vacuum-relief valve, such as a float valve that closes thefluidic channel when a vacuum is created and releases the fluidicchannel once the vacuum is released.

In another embodiment, the drug delivery device includes a compliantaccumulator reservoir downstream of the drug reservoir. This accumulatorincludes a compliant material that collapses and plugs the outlet portfrom the drug reservoir when the ambient pressure decreases below aspecified level. FIGS. 16A and 16B illustrates the mechanism ofoperation of the accumulator. FIG. 16A shows the concept during normaloperation. Drug from the drug reservoir 3 is pushed through an orifice75 and into the accumulator 79 prior to entering the nozzle tube 8 andthen exiting the nozzle via one-way valve 16. In FIG. 16B, an externalvacuum is applied to the environment that the device occupies. Thiscauses the accumulator 79 to collapse, blocking the orifice 75 from flowand halting flow through the nozzle 8. Another embodiment is a compliantmember that collapses with external vacuum pressure. A compliant tubing80 is placed in line and is in fluid communication with the drugreservoir 3 and the ambient environment. FIG. 16C shows the device innormal operation. FIG. 16D shows the collapsed compliant tubing 80 whenan external vacuum pressure is applied to the system, collapsing thecompliant tubing 80 and blocking flow from exiting the one-way valve 16.

FIGS. 17A, 17B, and 17C illustrate an additional mechanism that preventsbolus delivery in the mouth when a patient sucks on the drug deliverydevice, and changes in drug delivery rate when the ambient pressurechanges. FIG. 17A shows the concept during normal operation. Drug fromthe drug reservoir 3 is pushed through an orifice tube 81 prior toentering the nozzle tube 8 and then exiting the nozzle with one-wayvalve 16. In FIG. 17B, an external vacuum is applied to the environmentthat the device occupies. This causes the float valve 82 to compress thespring 83 and move in the direction of blocking flow from entering theorifice tube 81 and halting flow through the one-way valve 16. In FIG.17C, an external positive pressure is applied to the environment thatthe device occupies. This causes the float valve 82 to compress thespring 83 and move in the direction of blocking flow from exiting theorifice tube 81.

In preferred embodiments of these designs for substantiallyambient-pressure independent drug delivery devices, the drug deliverydevice is configured to deliver a bolus of less than about 5%, 3%, or 1%of the contents of a fresh drug reservoir, when the device is sucked onby a patient for a period of about one minute; or when the ambientpressure drops by about 2 psi for a period of about one minute.

Ambient-Temperature Independent Pump Designs and Methods

While the flow rate of electric pumps is typically substantiallyindependent of the ambient temperature the same is not true of passivepumps, such as elastomeric, spring-driven, gas-driven,propellant-driven, or osmotic pumps. The invention includes designs andmethods of achieving accurate drug delivery as the ambient temperaturesurrounding the drug delivery device increases or decreases, i.e.,devices that do not deliver clinically significant, undesired boluses asthe ambient temperature changes. Osmotic pumps, drug delivery patchesand other diffusion-based drug delivery systems are particularlysensitive to changes in the ambient temperature, and transienttemperature excursions may permanently change the drug transportcharacteristics of the diffusion-controlling membranes or pores in thesedevices. In a preferred embodiment the drug delivery devices of theinvention do not substantially change their average long-term rate ofdrug delivery after exposure to a transient temperature excursion. Inpreferred embodiments, the invention includes one or moretemperature-induced flow limiters which substantially reduce oreliminate the delivery of a drug bolus when a patient consumes a hotdrink.

FIG. 18A shows the temperature-time profile in the lower buccalvestibule when a hot drink is sipped. FIG. 18B shows thetemperature-time profile in the upper buccal vestibule when a hot drinkis sipped. FIG. 19A shows the temperature-time profile in the lowerbuccal vestibule when a cold drink is sipped. FIG. 19B shows thetemperature-time profile in the upper buccal vestibule when a cold drinkis sipped. All experiments were performed in a single male patient. Athermocouple was placed in the vestibular space to obtain baseline oraltemperature. A beverage was held in the mouth and swished over thelocation of the thermocouple for approximately three seconds. The datademonstrate that transient temperature excursions routinely occur in themouth when a hot or cold beverage is consumed, with excursions possibleof over about 53° C. and below about 24° C. The data also demonstratethat temperature excursions tend to be significantly reduced in theupper buccal vestibule than in the lower buccal vestibule, with amaximum temperature recorded of about 45° C. vs. 53° C. and a minimumtemperature recorded of 29° C. vs. 24° C. Consequently, in a preferredembodiment the drug delivery devices of the invention are located in theupper buccal vestibule rather than in the lower buccal vestibule.

Generally, it is a greater concern when the intra-oral temperatureincreases rather than decreases, because many non-electric pumps willprovide an undesired drug bolus that may be clinically significant. Whenthe temperature decreases, many non-electric pumps will provide atransient reduction in drug delivery that is generally not clinicallysignificant.

In a preferred embodiment, the drug delivery device is configured todeliver a bolus of less than 5% of the contents of a fresh drugreservoir, when immersed for five minutes or for one minute in a stirredphysiological saline solution at about 55° C. In another preferredembodiment, the drug delivery device is configured to change its averagerate of drug delivery over a period of one hour in a physiologicalsaline solution of pH 7 at 37° C. by less than about 5% after immersionfor five minutes or for one minute in a stirred physiological salinesolution at about 55° C., as compared to its average rate of drugdelivery immediately prior to exposure to the temperature excursion.

For elastomeric pumps, to minimize the change in flow rate when thepatient drinks a hot beverage, it is preferred to utilize elastomericmaterials whose force is relatively independent of temperature in therange of about 37° C. to about 55° C. For example, the force in a freshreservoir may increase by less than about 30%, 20%, or 10% when thetemperature is raised from about 37° C. to about 55° C. Examples ofelastomeric materials whose mechanical properties change little withinthese temperature ranges are natural rubbers, such as highlycross-linked polyisoprene and synthetic elastomers such as neoprene.

For spring-driven pumps, to minimize the change in drug administrationrate when the patient drinks a hot beverage, it is preferred to utilizespring materials whose force is relatively independent of temperature inthe range of about 37° C. to about 55° C. For example, the force in afresh reservoir may increase by less than 30%, 20%, or 10% when thetemperature is raised from about 37° C. to about 55° C. Examples ofmaterials with low sensitivity to temperature changes in this range,that are safe for use in the oral anatomy are 300 series stainlesssteels, such as 301, titanium, Inconel, and fully austenitic Nitinol(above its austenite finish temperature).

For gas-driven pumps, to minimize the change in flow rate when thepatient drinks a hot beverage, it is preferred to minimize the volume ofthe gas relative to the volume of the drug-including fluid. The volumeof the gas can be less than about 40%, 30%, 20%, or 10% of the volume ofthe drug-including fluid in a fresh reservoir. For example, the force ina fresh reservoir may increase by less than about 30%, 20%, or 10% whenthe temperature is raised from about 37° C. to about 55° C.

For propellant-driven pumps, it is preferred to use propellants whosevapor pressure increases by less than about 80%, 60%, or 40% when thetemperature is raised from about 37° C. to about 55° C. As examples, thevapor pressure of Dupont Dymel HFC-134a (1,1,1,2-tetrafluoroethane)increases from 938 kPa (absolute) at 37° C. to 1,493 kPa (absolute) at55° C., an increase of 59%. The vapor pressure of Dupont DymelHFC-227ea/P (1,1,1,2-tetrafluoroethane) increases from about 700 kPa(absolute) at 37° C. to 1,000 kPa (absolute) at 55° C., an increase of42%. In order to minimize the effect of temperature fluctuations on thepropellants, a number of methods can be employed. In one embodiment, aninsulating material can be used to decrease the sensitivity to changesin ambient temperature by insulating the propellant and drug reservoirswith materials of low thermal conductivity. Materials such as closedcell neoprene foams, can be used in this embodiment. In anotherembodiment, a material with very low thermal conductivity can beutilized, such as a ceramic.

Pump Automatic Stop/Start Safety Feature

When the pump is removed from the mouth, it is preferred that the drugdelivery be temporarily stopped. This is desirable so that drug is notwasted and, more importantly, so that dispensed drug does not accumulateon the surface of the device. Such an unquantified accumulation of drugon the surface of the device might lead to the undesired delivery of abolus of an unknown quantity of drug to the patient when the device isreinserted in the mouth. In preferred embodiments, the drug deliverydevice includes one or more automatic stop/start elements.

In one embodiment, the drug delivery device has an on/off switch orother mechanism for use by the patient. In a preferred embodiment, thedrug delivery device automatically stops delivering drug when (1) thedrug delivery device, the pump, and/or the oral liquid impermeablereservoir are removed from the mouth; (2) the drug delivery device, thepump, and/or the oral liquid impermeable reservoir are disconnected fromtheir attachment to the interior surface of the mouth, either directly(e.g., when secured to the teeth), or indirectly (e.g., when secured toa fastener which is secured to the teeth); or (3) the oral liquidimpermeable reservoir is disconnected from the pump or from the reusablecomponent (e.g., the fastener). In another preferred embodiment, thedrug delivery device automatically starts delivering drug when (1) thedrug delivery device, the pump, and/or the oral liquid impermeablereservoir are inserted into the mouth; (2) the drug delivery device, thepump, and/or the oral liquid impermeable reservoir are connected totheir attachment to the interior surface of the mouth, either directly(e.g., when secured to the teeth), or indirectly (e.g., when secured toa fastener which is secured to the teeth); or (3) the oral liquidimpermeable reservoir is connected to the pump or to the reusablecomponent (e.g., the fastener).

In another embodiment, the flow of drug begins when a cap is removedfrom the orifice from which the drug is delivered into the mouth andhalts when the cap is placed back onto the orifice. In a differentembodiment, a clip can be placed over the fluidic channel carrying thedrug, causing a kink or blockage, thereby halting the flow of drug tothe patient. The flow of drug is restored to the patient once the clipis removed. In yet another embodiment, the flow of drug is halted due tothe release of a pressure sensitive switch that breaks the circuit ofpower to the pump, halting the flow of drug when the device is removedfrom the mouth. The act of replacing the device back onto the dentitioncloses the pressure sensitive switch, restoring power to the pump andthe flow of drug to the patient. In a further embodiment, the fluidicchannel kinks, halting the flow of drug, when the device is removed fromthe patient due to a change in the radius of curvature of the fluidicchannel.

In another embodiment, illustrated in FIGS. 7E and 7F, a protrusion 84in the drug delivery device is attached to a spring loaded clutchmechanism 85 employed in the device that engages the piston 39 toinhibit the force transmission to the drug reservoir 3 prior to use.This protrusion 84 is depressed when the drug delivery device is placedonto the tooth or teeth, releasing the piston 39 and allowing the piston39 to transmit force to the drug reservoir 3. When the device is removedfrom the mouth, the protrusion 84 is disengaged, which again engages theclutch mechanism 85, stopping the piston 39 from applying force to thedrug reservoir 3.

In another embodiment, an actuator-connected sensor detects when thedevice is placed in the mouth. For example an optical sensor can send asignal to turn the device off, the connected actuator halting flow fromthe pump. In another example, an actuator-connected moisture sensor cansignal the connected actuator to turn the device on, initiating flowfrom the pump.

Concentrated Drug Formulations

Formulations of drugs to be delivered via the drug delivery devices ofthe invention (such as LD, LD prodrugs, DDC inhibitors, and other drugs)may include non-toxic aqueous or non-aqueous carrier liquids, such aswater, ethanol, glycerol, propylene glycol, polyethylene glycols, ethyllactate and edible oils such as vegetable oils, lipids, monoglycerides,diglycerides or triglycerides, paraffin oil, and their mixtures. Themonoglycerides, diglycerides or triglycerides can be of any non-toxiccarboxylic acid, the carboxylic acid having typically an even number ofcarbon atoms. The formulations may also include esters of non-toxicpolyols and carboxylic acids, such as carboxylic acids having an evennumber of carbon atoms. The esterified, partially esterified ornon-esterified non-toxic polyol can be, for example, erythritol,sorbitol, arabitol, lactitol, maltitol, mannitol and xylitol. Theliquids or their infused mixtures melt or sufficiently soften forpumping typically below about 37° C.

Formulations of the inventions are typically suspensions including oneor more drugs (which can be mostly solid particles) and a liquid (whichcan be an emulsion). The emulsion is typically an oil in water emulsionbut can also be a water in oil emulsion. The emulsion typicallyincludes: particles of the one or more drugs; water; a non-toxic,substantially water-insoluble organic compound that is liquid at 37° C.,or a mixture of substantially water insoluble organic compounds that areliquid at 37° C.; and at least one surfactant. The weight fraction ofthe solid drug can be greater than the weight fraction of thesubstantially water immiscible organic compound or mixture of organiccompounds; the weight fraction of the substantially water immiscibleorganic compounds or mixture of organic compounds can be greater thanthe weight fraction of water; and the weight fraction of the water canbe greater than the weight fraction of the surfactant or surfactants.Typically the weight fraction of the one or more mostly solid drugs inthe suspension can be greater than 0.3, such as greater than 0.4, suchas greater than 0.5, or such as greater than 0.6. The suspended soliddrug can include LD and/or CD. The weight fraction of the suspended LDcan be greater than the weight fraction of the suspended CD; it can be,for example, at least twice that of CD, such as at least three timesthat of CD. The density of the suspension can be greater than 1.1 g/cm³,for example it can be greater than 1.12 g/cm³, 1.15 g/cm³, 1.20 g/cm³,or 1.22 g/cm³. The water immiscible organic compound or mixture oforganic compounds can include, for example, triglycerides (exemplifiedby triglycerides of caproic acid and caprylic acid) or an oil (such ascanola oil).

In some embodiments the infused fluid can include drug-containingmicelles or liposomes.

Typically the continuous phase of the emulsion is hydrophilic and it canbe an oil in water emulsion, which is preferred because it is rapidlydispersed in saliva and other fluids of the gastrointestinal tract,which are aqueous. It can also be hydrophobic and it can be a water inoil emulsion. Typically the weight fraction of the oil in the emulsionis greater than the weight fraction of water. The weight fraction of theoil can be, for example, at least twice the weight fraction of water,for example the weight fraction of the oil can be three times the weightfraction of water or more, even when the continuous phase is water,i.e., the emulsion is an oil in water emulsion. The drug or drugs can bemostly solid, with only some drug dissolved in one of the carrier liquidemulsion phases, e.g., in the water phase of the emulsion.

The physical and chemical stability of suspensions including emulsions,particularly oil in water emulsions, can be superior to their stabilityin aqueous suspensions, i.e., in suspensions without oil. The superiorstability to oxidation by dissolved oxygen may be attributed to thelesser solubility of drugs like LD and CD in oil than in water and tothe greater viscosity of the emulsion, reducing the rate of reaction ofdiffusionally reacting dissolved molecules. Some liquids provide thebenefit of particularly low drug solubility, the low solubilityproviding the further benefit of slower Ostwald ripening when the drugparticles are small. In Ostwald ripening solid particles grow over timeby dissolution from highly curved (and therefore highly energetic)particle surfaces and their re-deposition on surfaces of largerparticles having with lower curvature.

In preferred embodiments, the intra-orally administered formulationincludes a suspension at body temperature, the suspension includingsolid drug particles of a concentration greater than or equal to 2 M,such as greater than 3 M, greater than 4 M, or greater than 4.4 M (e.g.,from 2 M to 4.4 M). For example, the concentration of the one or moredrugs in the suspension of the invention can be from about 35% (w/w) toabout 70% (w/w). The suspensions can remain free of sedimented soliddrug for about 1 month or more or for about 1 year or more at about 25°C. and 1 G. Accelerated testing of the suspensions for physicalstability can be conducted via centrifugation. For example, physicallystable suspensions can sustain centrifugation at 25° C. at about 16,000G (meaning 16,000 times the acceleration of sea level) gravity for atleast 30, 60, or 90 minutes without sedimenting or creaming.

In addition to the components described herein, the pharmaceuticalcompositions of the invention can further contain preservatives andantimicrobial agents such as benzoic acid, sodium benzoate, EDTA or itssalts, or other transition metal chelating agents or their salts,methylparaben, propylparaben, potassium sorbate, methyl hydroxybenzoate,or propyl hydroxybenzoate; and/or sweeteners like saccharine sodium,flavorings like citric acid, sodium citrate, and antifoaming ordefoaming agents like polydimethylsiloxanes and their combinations. Theymay also include poly-N-vinylpyrrolidone or polyethylene glycol.

Viscosity of the Suspensions

The suspensions may have a shear (dynamic) viscosity greater than 100Poise, or even greater than 1,000 Poise. For example, the suspensionsmay have viscosities of 100-1000 cP, 1,000-10,000 cP, 10,000-100,000 cP,100,000-500,000 cP, 500,000-2,500,000 cP, or greater than 2,500,000 cP.Typically the suspensions can't be poured at about 25° C., even thoughthey can easily deform under pressure.

Aqueous Phase

The suspensions of the invention are typically suspensions of solid drugparticles (e.g., solid LD and/or CD particles) in emulsions. Thesuspensions can contain less than or equal to about 16% (w/w) (e.g.,less than or equal to about 13% (w/w), less than or equal to about 11%(w/w), or less than or equal to about 9% (w/w)) of water. Thesuspensions of the invention can contain greater than or equal to about1% (w/w) (e.g., greater than or equal to about 2% (w/w) or greater thanor equal to about 3% (w/w)) of water. For example, the suspension cancontain between about 6% (w/w) and about 9% (w/w) water, such as about8% (w/w) of water. Even though the weight percentage of water is small,water or the aqueous phase may constitute the continuous phase of theemulsions, i.e., the emulsion in which solid drug particles aresuspended can be an oil in water emulsion, the oil droplets beingco-suspended in the continuous aqueous phase.

Water Immiscible Hydrophobic or Oil Phase

Suspensions of the invention include emulsions that include awater-immiscible hydrophobic phase. The hydrophobic (i.e., waterimmiscible) phase can be an oil. Exemplary oils include edible oils,such as vegetable oils; monoglycerides, diglycerides, or triglycerides;and paraffin oil. The oils can be coconut oil, palm oil, olive oil,soybean oil, sesame oil, corn oil, medium-chain triglycerides (MCT) oil,canola oil, or mineral oil. In certain embodiments, the oil ismedium-chain triglycerides (MCT) oil or canola oil. The oil can becoconut oil, or a medium chain triglyceride such as a Miglyol® (e.g.,Miglyol® 812). The oil can be a triglyceride of one or more C₆-C₂₄(e.g., C₈-C₁₆) fatty acids. Alternatively, the oil can be a triglycerideof C₈-C₁₂ fatty acids, C₁₄-C₁₈ fatty acids, or C₂₀-C₂₄ fatty acids, or amixture thereof. The suspension can contain less than or equal to about30% (w/w) (e.g., less than or equal to 29% (w/w), less than or equal toabout 27% (w/w), or less than or equal to about 25% (w/w)) of the oil.The suspension can contain greater than or equal to about 19% (w/w)(e.g., greater than or equal to about 21% (w/w) or greater than or equalto about 23% (w/w)) of the oil. The suspension can contain about 24%(w/w) of the oil. Even though the weight percentage of oil can begreater than that of water, the oil phase may not constitute thecontinuous phase of the emulsions, i.e., the emulsion can include acontinuous aqueous phase in which solid drug particles and oil dropletsare suspended.

Drug Particles

Drug particles for use in the pharmaceutical compositions of theinvention can be made by using any method known in the art for achievingthe desired particle size distributions. Useful methods include, forexample, milling, homogenization, supercritical fluid fracture, orprecipitation techniques. Exemplary methods are described in U.S. Pat.Nos. 4,540,602; 5,145,684; 5,518,187; 5,718,388; 5,862,999; 5,665,331;5,662,883; 5,560,932; 5,543,133; 5,534,270; and U.S. Pat. Nos.5,510,118; 5,470,583, each of which is specifically incorporated byreference.

In one approach, the drug, or a salt thereof, is milled in order toobtain micron or submicron particles. The milling process can be a dryprocess, e.g., a dry roller milling process, or a wet process, i.e.,wet-grinding. A wet-grinding process is described in U.S. Pat. Nos.4,540,602; 5,145,684; 6,976,647; and EP Patent Publication No. EP498482(the disclosures of which are hereby incorporated by reference). Thus,the wet grinding process can be practiced in conjunction with a liquiddispersion medium and dispersing or wetting agents such as described inthese publications. Useful liquid dispersion media include saffloweroil, ethanol, n-butanol, hexane, or glycol, among other liquids selectedfrom known organic pharmaceutical excipients (see U.S. Pat. Nos.4,540,602 and 5,145,684), and can be present in an amount of about2.0%-70%, 3%-50%, or 5%-25% by weight based on the total weight of thedrug in the formulation.

Drug particles can also be prepared by homogeneous nucleation andprecipitation in the presence of a wetting agent or dispersing agentusing methods analogous to those described in U.S. Pat. Nos. 5,560,932and 5,665,331, which are specifically incorporated by reference. Such amethod can include the steps of: (1) dispersing drug in a suitableliquid media; (2) adding the mixture from step (1) to a mixtureincluding at least one dispersing agent or wetting agent such that atthe appropriate temperature, the drug is dissolved; and (3)precipitating the formulation from step (2) using an appropriateanti-solvent. The method can be followed by removal of any formed salt,if present, by dialysis or filtration and concentration of thedispersion by conventional means. In one embodiment, the drug particlesare present in an essentially pure form and dispersed in a suitableliquid dispersion media. In this approach the drug particles are adiscrete phase within the resulting mixture. Useful dispersing agents,wetting agents, solvents, and anti-solvents can be experimentallydetermined.

Drug particles can also be prepared by high pressure homogenization (seeU.S. Pat. No. 5,510,118). In this approach drug particles are dispersedin a liquid dispersion medium and subjected to repeated homogenizationto reduce the size of the drug particles to the desired D₅₀ anddistribution. The drug particles can be reduced in size in the presenceof at least one or more dispersing agents or wetting agents.Alternatively, the drug particles can be contacted with one or moredispersing agents or wetting agents either before or after attrition.Other materials, such as a diluent, can be added to the drug/dispersingagent mixture before, during, or after the size reduction process. Forexample, unprocessed drug can be added to a liquid medium in which it isessentially insoluble to form a premix (i.e., about 0.1%-60% w/w drug,and about 20%-60% w/w dispersing agents or wetting agents). Inparticular embodiments, the dispersing agent is a surfactant (e.g., anon-ionic surfactant). The apparent viscosity of the premix suspensionis preferably less than about 1,000 cP. The premix can then betransferred to a microfluidizer and circulated continuously first at lowpressures, and then at maximum capacity (i.e., 3,000 to 30,000 psi)until the desired particle size reduction is achieved. The resultingdispersion of drug particles can be included in a pharmaceuticalcomposition of the invention.

The drug particles can be prepared with the use of one or more wettingand/or dispersing agents, which are, e.g., adsorbed on the surface ofthe drug particle. The drug particles can be contacted with wettingand/or dispersing agents either before, during, or after size reduction.Generally, wetting and/or dispersing agents fall into two categories:non-ionic agents and ionic agents. The most common non-ionic agents areexcipients which are contained in classes known as binders, fillers,surfactants and wetting agents. Limited examples of non-ionic surfacestabilizers are hydroxypropylmethylcellulose, polyvinylpyrrolidone,Plasdone, polyvinyl alcohol, Pluronics, Tweens and polyethylene glycols(PEGs). Ionic agents are typically organic molecules bearing an ionicbond such that the molecule is charged in the formulation, such as longchain sulfonic acid salts (e.g., sodium lauryl sulfate and dioctylsodium sulfosuccinate) or fatty acid salts.

The drug particles can include, for example, LD and/or CD, and mayoptionally further include a COMT inhibitor.

The drug particles present in the suspension of the invention can besized to have D₅₀ less than or equal to 500 μm, e.g., less than or equalto 250 μm, 200 μm, 150 μm, 100 μm, 75 μm, or 50 μm. The drug particlespresent in the suspension of the invention can be sized to have D₅₀greater than or equal to 1 μm, e.g., greater than or equal to 3 μm, 5μm, 10 μm, or 25 μm. In some embodiments, the drug particles are sizedto have D₅₀ in the range of from about 1 μm to about 500 μm (e.g., fromabout 3 μm to about 250 μm, from about 10 μm to about 250 μm, from about25 μm to about 200 μm, from about 3 μm to about 100 μm, from about 5 μmto about 50 μm, or from about 7 μm to about 30 μm). In particularembodiments, the drug particles are sized to have D₅₀ in the range offrom about 1 μm to about 25 μm (e.g., from 1 μm to about 10 μm). Incertain embodiments, the drug (e.g., LD or CD) particles can be sized tohave D₅₀ less than or equal to about 75 μm. In further embodiments, thedrug (e.g., LD or CD) particles can be sized to have D₉₀ less than orequal to about 20 μm, 50 μm, 100 μm, 150 μm, 200 μm, or 250 μm. Incertain embodiments, the drug (e.g., LD or CD) particles can be sized tohave D₁₀ less than or equal to about 1 μm, 5 μm, or 25 μm. In certainembodiments, the drug (e.g., LD or CD) particles can be sized to haveD₉₅ less than or equal to about 100 μm (such as less than 50 μm) and/ora D₈₀ less than or equal to about 30 μm or about 45 μm.

The maximal solid drug particle diameters may be bimodally ormultimodally distributed.

When the pharmaceutical composition is infused and the flow iscontrolled by a flow-limiting tube or orifice, the peak diameter of thelargest particles of the unimodal, bimodal or multimodal particle sizedistribution is typically smaller than 1/10^(th) of its diameter, inorder to avoid blockage. Typically, less than about 3% of the particlesof the distribution, for example less than 1% of the particles, havediameters that are larger than ⅕^(th) of the diameter of theflow-controlling component of the drug delivery device. For example whenthe diameter of the flow controlling nozzle, orifice or pipe is 1 mmthen fewer than 3% or 1% of the particles have diameters greater thanabout 200 μm, 150 μm, 125 μm, 100 μm, 75 μm, or 50 μm. Typically, thepeak of the particle distribution, or when the distribution ismultimodal the peak of the distribution of the largest particles, can beof 100 μm or less, for example 50 μm or less, 30 μm or less, or 10 μm orless, or 3 μm or less. In a bimodal distribution the peaks for thesmaller particles might be correspondingly about 20 μm or less, 6 μm orless, 2 μm or less or 0.6 μm or less, respectively. Typically theinfused suspensions include both LD and CD. The LD particles can belarger than the CD particles (or vice versa) wherefore the particle sizedistribution can be bimodal. For example the diameters of the LDparticles can peak in the distribution at diameters 1.5 times or evenlarger than the peak diameters of CD particles. The resulting bimodaldistribution can provide for denser packing of solid particles in theemulsion, can increase the concentration of the drug, reduce the size ofthe reservoir containing the daily dose, and reduce the likelihood offlow-impeding aggregation of the particles.

Surfactants

The suspensions of the invention can contain a surfactant in an amountsufficient to provide physical stability adequate for continuous orfrequent intermittent intraoral administration of the pharmaceuticalcomposition of the invention. The surfactant can be selected based onits hydrophilic-lipophilic balance (HLB) to match the surface propertiesof drug particles and the continuous phase (e.g., of water). Thesurfactant can be an ionic or a neutral surfactant. In general,non-ionic surfactants are preferred and surfactants where thehydrophilic function includes polyethylene oxide are especiallypreferred.

Non-limiting examples of ionic surfactants are sodium dodecyl sulfate(SDS), phospholipids (e.g., lecithin), quaternary ammonium salts (e.g.,cetrimonium bromide), pyridinium salts (e.g., cetylpyridinium chloride),and fatty acid salts. Non-limiting examples of non-ionic surfactants arepoloxamers (also known under tradenames Cremophor®, Kolliphor®, Lutrol®,Pluronic®, and Synperonic®), poloxamines, polysorbates (also known undertradename Tween®), fatty acid esters of sorbitan (also known undertradename Span®), polyethylene glycol alkyl ethers (also known undertradename Brij®), fatty acid esters of polyethylene glycol (also knownunder tradenames Solutol® and Myrj®), alkyl polyglycosides (e.g., alkylpolyglucosides (also known under tradenames Triton® and Ecoteric®)), andfatty acid monoglycerides (e.g., monolaurin).

The suspension of the invention can contain a surfactant that is anemulsifier (e.g., a hydrophobic emulsifier (such as a surfactant havingHLB from 3 to 8) or a hydrophilic emulsifier (such as a surfactanthaving HLB from 10 to 18)). In certain embodiments, the surfactant is apoloxamer or a polysorbate. The suspension of the invention can containless than or equal to about 7% (w/w) (e.g., less than or equal to about6% (w/w) or less than or equal to about 5% (w/w)) of the surfactant. Thesuspension of the invention can contain greater than or equal to about2% (w/w) (e.g., greater than or equal to about 2% (w/w) or greater thanor equal to about 4% (w/w)) of the surfactant. In particularembodiments, the suspension of the invention contains about 5% (w/w) ofthe surfactant.

The surfactant may be selected from a wide variety of soluble non-ionicsurface active agents including surfactants that are generallycommercially available under the IGEPAL™ trade name from GAF Company.The IGEPAL™ liquid non-ionic surfactants are polyethylene glycolp-isooctylphenyl ether compounds and are available in various molecularweight designations, for example, IGEPAL™ CA720, IGEPAL™ CA630, andIGEPAL™ CA890. Other suitable non-ionic surfactants include thoseavailable under the trade name TETRONIC™ 909 from BASF WyandotteCorporation. This material is a tetra-functional block copolymersurfactant terminating in primary hydroxyl groups. Suitable non-ionicsurfactants are also available under the VISTA ALPHONIC™ trade name fromVista Chemical Company and such materials are ethoxylates that arenon-ionic biodegradables derived from linear primary alcohol blends ofvarious molecular weights. The surfactant may also be selected frompoloxamers, such as polyoxyethylene-polyoxypropylene block copolymers,such as those available under the trade names Synperonic PE series(ICI), Pluronic® series (BASF), Supronic, Monolan, Pluracare™, andPlurodac™; polysorbate surfactants, such as Tween® 20 (PEG-20 sorbitanmonolaurate); nonionic detergents (e.g., nonyl phenoxypolyethoxylethanol(NP-40), 4-octylphenol polyethoxylate (Triton-X100™), Brij nonionicsurfactants); and glycols such as ethylene glycol and propylene glycol.In particular embodiments, the surfactant is a non-ionic surfactantincluding a polyglycolized glyceride, a poloxamer, an alkyl saccharide,an ester saccharide, a polysorbate surfactant, or a mixture thereof.

The weight fraction of the one or more solid drugs in the suspension canbe greater than about 0.6. The suspension can be non-pourable. Thesuspensions can be pumped or extruded into the mouth, for example, byslippage also known as plug-flow, or by a combination of flow andslippage. Slippage or plug-flow means that parts of the suspension, oreven all of the suspension move, e.g., through a flow-controlling tubeor orifice as a unit or as multiple units, each unit a plasticallydeformable block such as a cylindrical block. The movement, i.e., flowof the block or blocks can be retarded by friction between the movingblock and the wall of the flow-controlling tube. An optional lubricantcan reduce the friction and facilitate the extrusion as described below.

Pharmaceutical compositions including the drugs in Table A may beformulated using a variety of formulations. Five formulations (A, B, C,D, and F) for these and other drugs are described below.

Type A Formulations

Type A formulations are pharmaceutical compositions including asuspension, which is typically a highly viscous but neverthelessextrudable paste, the suspension including

(i) from about 35% to about 80% (w/w) (e.g., from about 35% to about70%, from about 35% to about 65%, from about 35% to about 60%, fromabout 35% to about 55%, from about 35% to about 50%, from about 35% toabout 45%, from about 35% to about 40%, from about 40% to about 45%,from about 40% to about 45%, from about 40% to about 50%, from about 40%to about 55%, from about 40% to about 60%, from about 40% to about 65%,from about 40% to about 65%, from about 40% to about 70%, from about 40%to about 75%, from about 45% to about 75%, from about 50% to about 75%,from about 55% to about 75%, from about 60% to about 75%, from about 65%to about 75%, from about 70% to about 75%, or from about 50% to about65%) undissolved solid drug particles and dissolved drugs, or salts ofthe solid or dissolved drugs, the solid drugs or their salts decomposingwithout melting, or melting above 45° C., or softening above 45° C.;

(ii) from about 19% to about 40% (w/w) (e.g., from about 19% to about28%, from about 19% to about 26%, from about 19% to about 24%, fromabout 19% to about 22%, from about 19% to about 21%, from about 21% toabout 24%, from about 21% to about 30%, from about 24% to about 30%,from about 26% to about 30%, from about 28% to about 30%, or from about31% to about 40%) of one or more water-immiscible compounds melting orsoftening at or below 45° C.,

(iii) from about 2% to about 40% (w/w) (e.g., from about 2% to about15%, from about 2% to about 13%, from about 2% to about 12%, from about2% to about 10%, from about 2% to about 8%, from about 2% to about 6%,from about 2% to about 4%, from about 4% to about 13%, from about 6% toabout 13%, from about 8% to about 13%, from about 6% to about 10%, fromabout 10% to about 13%, —from about 13% to about 16%, from about 16% toabout 25%, from about 25% to about 30%, or from about 31% to about 40%)water, and

(iv) from about 1% to about 10% (w/w) (e.g., from about 1% to about 7%,from about 1% to about 5%, from about 1% to about 3%, from about 3% toabout 8%, or from about 5% to about 8%) surfactant, wherein thepharmaceutical composition is physically stable and suitable forcontinuous or frequent intermittent intra-oral delivery.

In some embodiments, the Type A formulations include at about 25° C.greater than about 500 mg/mL of the drug, e.g., between about 500 mg/mLand about 850 mg/mL of the drug.

In some embodiments, the pharmaceutical composition includes a drugparticle-containing emulsion. In other embodiments, the solid drugparticle containing pharmaceutical composition can be macroscopicallysubstantially homogeneous, when examined at a resolution of 5 mm, 3 mm,1 mm, or 0.5 mm. In any of the preceding aspects, the suspension may bean extrudable, non-pourable emulsion. In some embodiments, thesuspension is physically stable for about 12 months at about 5° C. Inother embodiments, the suspension is physically stable for about 12months at about 25° C. In certain embodiments, after 12 months (e.g.,after 13 months, after 14 months, after 15 months, or more) thesuspension is physically stable for about 48 hours at about 37° C.

In any of the preceding Type A formulations, the pharmaceuticalcomposition may include a continuous hydrophilic phase.

In any of the preceding Type A formulations, the concentration of drugin a pharmaceutical composition may be at least 1.75 M (e.g, more than1.80 M, 1.85 M, 1.90 M, 1.95 M, 2.0 M, 2.5 M, 3.0 M, or even 3.5 M). Insome embodiments, the pharmaceutical composition includes from about 50%to about 70% (w/w) (e.g., from about 50% to about 65%, from about 50% toabout 60%, from about 50% to about 55%, from about 55% to about 70%,from about 60% to about 70%, or from about 65% to about 70%) drugparticles, the concentration of drug in the pharmaceutical compositionbeing at least 3.0 M (e.g., 3.1 M, 3.2 M, 3.5 M, or more).

In some embodiments, the suspension of any of the preceding aspectsincludes one or more water-immiscible compounds that melts or softensbelow 45° C. (e.g., at 40° C., 37° C., 35° C., or less). In someembodiments, the weight ratio of the one or more water-immisciblecompounds to water is greater than 1.0 (e.g., greater than 1.5, greaterthan 2.0, greater than 3.0, or greater than 5.0).

In some embodiments, the one or more water-immiscible compounds of anyof the preceding aspects includes an oil. In some embodiments, thesuspension includes a continuous hydrophilic phase. In certainembodiments, the suspension includes an oil in water emulsion. In someembodiments, the suspension is free of polymers of a molecular massgreater than 1,000 Daltons (e.g., greater than about 1,100 Daltons,greater than about 1,200 Daltons, greater than about 1,500 Daltons,greater than about 1,700 Daltons, or greater than about 2,000 Daltons).In some embodiments, the suspension has a dynamic viscosity of at least100 cP (e.g., greater than 500 cP, 1,000 cP, 5,000 cP, 10,000 cP, 50,000cP, or 100,000 cP) at 37° C.

In any of the preceding Type A formulations, the suspension may includegreater than 50% (w/w) (e.g., greater than 55%, greater than 60%,greater than 65%, or greater than 70%) drug particles. In someembodiments, the D₅₀ of the drug particles is less than or equal toabout 500 μm, about 250 μm, about 200 μm, about 150 μm, about 125 μm, orabout 100 μm. In some embodiments, the D₅₀ of the drug particles isgreater than or equal to about 1 μm, about 3 μm, about 5 μm, about 10μm, or about 25 μm. In particular embodiments, the D₅₀ of the drugparticles is 25±24 μm; 1-10 μm; 11-20 μm; 21-30 μm; 31-40 μm; or 41-50μm. In other embodiments, the D₅₀ of the drug particles is 75±25 μm;51-75 μm; or 76-100 μm. In certain embodiments, the D₅₀ of the drugparticles is 125±25 μm. In further embodiments, the D₅₀ of the drugparticles is 175±25 μm.

In any of the preceding Type A formulations, the suspension may includeless than or equal to about 40% (w/w), such as less than about 35%(w/w), about 25% (w/w), 16% (w/w), about 13% (w/w), about 12% (w/w),about 11% (w/w), or about 9% (w/w) water. In some embodiments, thesuspension includes greater than or equal to about 1% (w/w), about 2%(w/w), or about 3% (w/w) water. In certain embodiments, the suspensionincludes 4±2% (w/w) water. In particular embodiments, the suspensionincludes 8±2% (w/w) water. In other embodiments, the suspension includes13±3% (w/w) water. In some embodiments the suspension includes 25±15%(w/w) water.

In any of the preceding Type A formulations, the one or morewater-immiscible compounds may include an oil selected from a saturatedfatty acid triglyceride, an unsaturated fatty acid triglyceride, a mixedsaturated and unsaturated fatty acid triglyceride, a medium-chain fattyacid triglyceride, canola oil, coconut oil, palm oil, olive oil, soybeanoil, sesame oil, corn oil, or mineral oil. In some embodiments, the oilis a saturated fatty acid triglyceride. In other embodiments, the oil isa medium-chain fatty acid triglyceride oil. For example, the oil can bea Miglyol® or chemical equivalent. In certain embodiments, the oil is acanola oil. In particular embodiments, the oil is a coconut oil. In someembodiments, the oil is a triglyceride or one or more C₆-C₂₄ fattyacids, such as a triglyceride of one or more C₈-C₁₆ fatty acids. Forexample, the oil can be a triglyceride of C₈-C₁₂ fatty acids, C₁₄-C₁₈fatty acids, or C₂₀-C₂₄ fatty acids, or a mixture thereof. In someembodiments, at least 50% (w/w) of the one or more water-immisciblecompounds is a triglyceride of one or more C₈-C₁₂ fatty acids. Incertain embodiments, the suspension includes less than or equal to about30% (w/w) (e.g., about 29% (w/w), about 27% (w/w), or about 25% (w/w))of the oil. In particular embodiments, the suspension includes greaterthan or equal to about 19% (w/w) (e.g., about 21% (w/w), or about 23%(w/w)) of the oil. In certain embodiments, the suspension includes 20±2%(w/w) of the oil. In other embodiments, the suspension includes 24±2%(w/w) of the oil. In some embodiments, the suspension includes 28±2%(w/w) of the oil.

In any of the preceding Type A formulations, the pharmaceuticalcomposition may include a surfactant. A surfactant of a pharmaceuticalcomposition may be a non-ionic surfactant. In some embodiments, thenon-ionic surfactant includes a polyglycolized glyceride, a poloxamer,an alkyl saccharide, an ester saccharide, or a polysorbate surfactant.In certain embodiments, the non-ionic surfactant includes a poloxamer.In other embodiments, the non-ionic surfactant includes a polyglycolizedglyceride that is a polyethoxylated castor oil. In particularembodiments, the non-ionic surfactant includes a polysorbate surfactantthat is Polysorbate 60. In some embodiments, the suspension includesless than or equal to about 10% (w/w) (e.g., about 9% (w/w), 8% (w/w),7% (w/w), about 6% (w/w), or about 5% (w/w)) of the surfactant. In someembodiments, the suspension includes greater than or equal to about 2%(w/w) (e.g., about 3% (w/w) or about 4% (w/w)) of the surfactant. Incertain embodiments, the suspension includes about 6±3% (w/w) of thesurfactant.

In some embodiments of the Type A formulations, a pharmaceuticalcomposition of any of the preceding aspects further includes anantioxidant such as Vitamin E, TPGS, ascorbylpalmitate, a tocopherol,thioglycerol, thioglycolic acid, cysteine, N-acetyl cysteine, vitamin A,propyl gallate, octyl gallate, butylhydroxyanisole, orbutylhydroxytoluene. In some embodiments, the antioxidant is oilsoluble. In other embodiments, the pH of the suspension of any of thepreceding aspects is less than or equal to about 7.0, about 5.0, orabout 4.0. In certain embodiments, the pH is greater than or equal toabout 3.0. In some embodiments, the shelf life of the pharmaceuticalcomposition is 1 year or longer at 5±3° C. In particular embodiments,the shelf life of the pharmaceutical composition is 1 year or longer at25±3° C.

In any of the preceding Type A formulations, the suspension may notcream or sediment when centrifuged for 1 hour at an acceleration ofabout 5,000 G or greater (e.g., about 7,000 G, about 9,000 G, about10,000 G, or about 16,000 G) at 25±3° C. In some embodiments, thepharmaceutical composition does not cream or sediment when stored for 12months at 5±3° C. or 25±3° C. In some embodiments, after thecentrifugation or storage the concentrations of drug in the layercontaining the top 20 volume % and the layer containing the bottom 20volume % of the composition differ by less than 10%. In particularembodiments, after the centrifugation or storage the concentrations ofdrug in the layer containing the top 20 volume % and the layercontaining the bottom 20 volume % of the composition differ by less than6% (e.g., 5%, 4%, 3%, 2%, 1%, or less). In any of these embodiments,after the centrifugation or storage a pharmaceutical composition mayexhibit no visible creaming or sedimentation.

In any of the preceding Type A formulations, the pharmaceuticalcomposition may have substantially no taste.

Type A formulations typically include at about 25° C. (a) between 500mg/mL and 850 mg/mL of the drug when the drug is mostly or entirely acompound having a density of about 1.7 g/mL or less, e.g., of betweenabout 1.3 g/mL and about 1.7 g/mL; (b) when the formulation includes acompound of a metal, such as a compound of magnesium, zinc or iron, thedensity of which can exceed about 1.7 g/mL, then the composition caninclude more than 850 mg/mL of the drug, such as between 850 mg/mL andabout 2.5 g/mL. The density of the formulations at about 25° C. can begreater than about 1.15 g/mL, such as greater than 1.20 g/mL, such as1.25 g/mL or greater. The formulations can be non-pourable at about 25°C. but can be extruded at body temperature, typically 37±2° C.

An exemplary physically stable paste composition of an organic compounddrug can include about 60-64 weight % of the drug, 23-26 weight % of anoil like Miglyol 812™, 7-9 weight % of water, and 4-6 weight % of asurfactant like Poloxamer 188. An exemplary physically stable pastecomposition of an inorganic or metal-organic compound drug, such as acompound of magnesium or zinc, can include about 60-80 weight % of thedrug, 8-26 weight % of an oil like Miglyol 812™, 3-15 weight % of waterand 2-6 weight % water of a surfactant like Poloxamer 188.

Type B Formulations

Type B formulations are pharmaceutical compositions including asuspension, the suspension including

(i) from about 25% to about 80% (w/w) (e.g., from about 25% to about35%, from about 35% to about 70%, from about 35% to about 65%, fromabout 35% to about 60%, from about 35% to about 55%, from about 35% toabout 50%, from about 35% to about 45%, from about 35% to about 40%,from about 40% to about 45%, from about 40% to about 45%, from about 40%to about 50%, from about 40% to about 55%, from about 40% to about 60%,from about 40% to about 65%, from about 40% to about 65%, from about 40%to about 70%, from about 40% to about 75%, from about 45% to about 75%,from about 50% to about 75%, from about 55% to about 75%, from about 60%to about 75%, from about 65% to about 75%, from about 70% to about 75%,or from about 50% to about 65%) of one or more solid excipients.

(ii) from about 5% to about 60% (w/w) (e.g., from about 5% to about 10%,from about 11% to about 20%, from about 21% to about 30%, from about 31%to about 40%, from about 41% to about 50%, from about 51% to about 50%,from about 51% to about 60%,) drug particles, or salts thereof;

(iii) from about 19% to about 30% (w/w) (e.g., from about 19% to about28%, from about 19% to about 26%, from about 19% to about 24%, fromabout 19% to about 22%, from about 19% to about 21%, from about 21% toabout 24%, from about 21% to about 30%, from about 24% to about 30%,from about 26% to about 30%, or from about 28% to about 30%) of one ormore water-immiscible compounds;

(iv) from about 2% to about 25% (w/w) (e.g., from about 2% to about 20%,from about 2% to about 15%, from about 2% to about 13%, from about 2% toabout 12%, from about 2% to about 10%, from about 2% to about 8%, fromabout 2% to about 6%, from about 2% to about 4%, from about 4% to about13%, from about 6% to about 25%, from about 6% to about 20%, from about6% to about 13%, from about 8% to about 13%, from about 6% to about 10%,from about 10% to about 13%, from about 13% to about 16% from about 13%to about 25%, from about 17% to about 25%) water; and

(v) from about 1% to about 10% (w/w) (e.g., from about 1% to about 7%,from about 1% to about 5%, from about 1% to about 3%, from about 3% toabout 8%, or from about 5% to about 8%) surfactant;

wherein the pharmaceutical composition is physically stable and suitablefor continuous or frequent intermittent intra-oral delivery; and

In some embodiments, the Type B formulations include at about 25° C.between about 50 mg/mL and about 500 mg/mL of the drug. In someembodiments, the Type B formulations include between 200 mg/mL and about800 mg/mL (such as between 200 mg/mL and 750 mg/mL) of the solidexcipient.

In some embodiments of the Type B formulations, the solid excipientincludes an organic compound. Exemplary organic excipients includecellulose and its derivatives, such as non-swelling cellulosederivative, or amino acids like L-tyrosine or L-phenylalanine. In otherembodiments the solid excipient includes an inorganic excipient, such astitanium dioxide or calcium silicate, or calcium phosphate, which can beof higher density and its weight percentage can exceed 80% (w/w).

In some embodiments of the Type B formulations, the solid drug particlecontaining pharmaceutical composition includes a drugparticle-containing emulsion. In other embodiments, the pharmaceuticalcomposition is macroscopically substantially homogeneous when examinedat a resolution of 5 mm, 3 mm, 1 mm, or 0.5 mm. In any of the precedingaspects, the suspension may be an extrudable, non-pourable emulsion. Insome embodiments, the suspension is physically stable for about 12months at about 5° C. In other embodiments, the suspension is physicallystable for about 12 months at about 25° C. In certain embodiments, after12 months (e.g., after 13 months, after 14 months, after 15 months, ormore) the suspension is physically stable for about 48 hours at about37° C.

In any of the preceding Type B formulations, the pharmaceuticalcomposition may include a continuous hydrophilic phase.

In any of the preceding aspects, the concentration of drug in apharmaceutical composition may be between 0.15 M and 1.0 M (e.g.,0.15-0.25M, 0.25-0.35M, 0.35-0.45M, 0.45-0.55M, 0.55-0.65M, 0.65-0.75M,0.75-0.85M, or 0.85-1.0 M).

In some embodiments of the Type B formulations, the suspension of any ofthe preceding aspects includes one or more water-immiscible compoundsthat melts or softens below 45° C. (e.g., at 40° C., 37° C., 35° C., orless). In some embodiments, the weight ratio of the one or morewater-immiscible compounds to water is greater than 1.0 (e.g., greaterthan 1.5, greater than 2.0, greater than 3.0, or greater than 5.0).

In some embodiments of the Type B formulations, the one or morewater-immiscible compounds of any of the preceding aspects includes anoil. In some embodiments, the suspension includes a continuoushydrophilic phase including greater than 50% (w/w) (e.g., 55%, 60%, 65%,70%, or 75%) drug particles. In certain embodiments, the suspensionincludes an oil in water emulsion. In some embodiments, the suspensionis free of polymers of a molecular mass greater than 1,000 Daltons(e.g., greater than about 1,100 Daltons, greater than about 1,200Daltons, greater than about 1,500 Daltons, greater than about 1,700Daltons, or greater than about 2,000 Daltons). In some embodiments, thesuspension has a dynamic viscosity of at least 100 cP (e.g., greaterthan 500 cP, 1,000 cP, 5,000 cP, 10,000 cP, 50,000 cP, or 100,000 cP) at37° C.

In some embodiments of the Type B formulations, the D₅₀ of the drugparticles and/or of the one or more solid excipients is less than orequal to about 500 μm, about 250 μm, about 200 μm, about 150 μm, about125 μm, or about 100 μm. In some embodiments, the D₅₀ of the drugparticles and/or of the one or more solid excipients is greater than orequal to about 1 μm, about 3 μm, about 5 μm, about 10 μm, or about 25μm. In particular embodiments, the D₅₀ of the drug particles and/or ofthe one or more solid excipients is 25±24 μm; 1-10 μm; 11-20 μm; 21-30μm; 31-40 μm; or 41-50 μm. In other embodiments, the D₅₀ of the drugparticles and/or of the one or more solid excipients is 75±25 μm; 51-75μm; or 76-100 μm. In certain embodiments, the D₅₀ of the drug particlesand/or of the one or more solid excipients is 125±25 μm. In furtherembodiments, the D₅₀ of the drug particles and/or of the one or moresolid excipients is 175±25 μm.

In any of the preceding Type B formulations, the suspension may includeless than or equal to about 16% (w/w), about 13% (w/w), about 12% (w/w),about 11% (w/w), or about 9% (w/w) water. In some embodiments, thesuspension includes greater than or equal to about 1% (w/w), about 2%(w/w), or about 3% (w/w) water. In certain embodiments, the suspensionincludes 4±2% (w/w) water. In particular embodiments, the suspensionincludes 8±2% (w/w) water. In other embodiments, the suspension includes13±3% (w/w) water.

In any of the preceding Type B formulations, the one or morewater-immiscible compounds may include an oil selected from a saturatedfatty acid triglyceride, an unsaturated fatty acid triglyceride, a mixedsaturated and unsaturated fatty acid triglyceride, a medium-chain fattyacid triglyceride, canola oil, coconut oil, palm oil, olive oil, soybeanoil, sesame oil, corn oil, or mineral oil. In some embodiments, the oilis a saturated fatty acid triglyceride. In other embodiments, the oil isa medium-chain fatty acid triglyceride oil. For example, the oil can bea Miglyol® or chemical equivalent. In certain embodiments, the oil is acanola oil. In particular embodiments, the oil is a coconut oil. In someembodiments, the oil is a triglyceride or one or more C₆-C₂₄ fattyacids, such as a triglyceride of one or more C₈-C₁₆ fatty acids. Forexample, the oil can be a triglyceride of C₈-C₁₂ fatty acids, C₁₄-C₁₈fatty acids, or C₂₀-C₂₄ fatty acids, or a mixture thereof. In someembodiments, at least 50% (w/w) of the one or more water-immisciblecompounds is a triglyceride of one or more C₈-C₁₂ fatty acids. Incertain embodiments, the suspension includes less than or equal to about30% (w/w) (e.g., about 29% (w/w), about 27% (w/w), or about 25% (w/w))of the oil. In particular embodiments, the suspension includes greaterthan or equal to about 19% (w/w) (e.g., about 21% (w/w), or about 23%(w/w)) of the oil. In certain embodiments, the suspension includes 20±2%(w/w) of the oil. In other embodiments, the suspension includes 24±2%(w/w) of the oil. In some embodiments, the suspension includes 28±2%(w/w) of the oil.

In any of the preceding Type B formulations, the pharmaceuticalcomposition may include a surfactant. A surfactant of a pharmaceuticalcomposition may be a non-ionic surfactant. In some embodiments, thenon-ionic surfactant includes a polyglycolized glyceride, a poloxamer,an alkyl saccharide, an ester saccharide, or a polysorbate surfactant.In certain embodiments, the non-ionic surfactant includes a poloxamer.In other embodiments, the non-ionic surfactant includes a polyglycolizedglyceride that is a polyethoxylated castor oil. In particularembodiments, the non-ionic surfactant includes a polysorbate surfactantthat is Polysorbate 60. In some embodiments, the suspension includesless than or equal to about 8% (w/w) (e.g., about 7% (w/w), about 6%(w/w), or about 5% (w/w)) of the surfactant. In some embodiments, thesuspension includes greater than or equal to about 2% (w/w) (e.g., about3% (w/w) or about 4% (w/w)) of the surfactant. In certain embodiments,the suspension includes about 5±2% (w/w) of the surfactant.

In some embodiments of the Type B formulations, a pharmaceuticalcomposition of any of the preceding aspects further includes anantioxidant such as Vitamin E, TPGS, ascorbylpalmitate, a tocopherol,thioglycerol, thioglycolic acid, cysteine, N-acetyl cysteine, vitamin A,propyl gallate, octyl gallate, butylhydroxyanisole, orbutylhydroxytoluene. In some embodiments, the antioxidant is oilsoluble. In other embodiments, the pH of the suspension of any of thepreceding aspects is less than or equal to about 7.0, about 5.0, orabout 4.0. In certain embodiments, the pH is greater than or equal toabout 3.0. In some embodiments, the shelf life of the pharmaceuticalcomposition is 1 year or longer at 5±3° C. In particular embodiments,the shelf life of the pharmaceutical composition is 1 year or longer at25±3° C.

In any of the preceding Type B formulations, the suspension may notcream or sediment when centrifuged for 1 hour at an acceleration ofabout 5,000 G or greater (e.g., about 7,000 G, about 9,000 G, about10,000 G, or about 16,000 G) at 25±3° C. In some embodiments, thepharmaceutical composition does not cream or sediment when stored for 12months at 5±3° C. or 25±3° C. In some embodiments, after thecentrifugation or storage the concentrations of drug in the layercontaining the top 20 volume % and the layer containing the bottom 20volume % of the composition differ by less than 10%. In particularembodiments, after the centrifugation or storage the concentrations ofdrug in the layer containing the top 20 volume % and the layercontaining the bottom 20 volume % of the composition differ by less than6% (e.g., 5%, 4%, 3%, 2%, 1%, or less). In any of these embodiments,after the centrifugation or storage a pharmaceutical composition mayexhibit no visible creaming or sedimentation.

In any of the preceding Type B formulations, the pharmaceuticalcomposition may have substantially no taste.

The density of the formulations at about 25° C. can be greater thanabout 1.15 g/mL, such as greater than 1.20 g/mL, such as 1.25 g/mL orgreater. The formulations can be non-pourable at about 25° C., but canbe extruded at body temperature, typically 37±2° C.

An exemplary physically stable paste composition where the excipient isan amino acid like L-tyrosine can include about 10-15 weight % of thedrug, 45-55 weight % of the excipient, 23-26 weight % of an oil likeMiglyol 812, 7-9 weight % of a surfactant like Poloxamer 188, and 4-6weight % water. Another exemplary physically stable paste composition,where the excipient is non-swelling cellulose derivative, can include5-12 weight % of the drug, 20-30 weight % excipient, 20-30 weight %water, 7-9 weight % of a surfactant like Kolliphor RH40, and 25-35weight % of an oil like Miglyol™ 812. The paste can be non-pourable atabout 25° C. and can be extruded at about 37° C. into the mouth,

Type C Formulations

Type C formulations include between 20 mg/mL and 150 mg/mL (for examplebetween 20 mg/mL and 100 mL, or between 20 mg/mL and 50 mg/mL) of thedrug. Type C formulations include true solutions, oil-in-water emulsionsor water-in-oil emulsions, or solid particle including suspensions. Theformulations can include an excipient that is liquid at or below about45° C., such as at or below 37° C. Examples of such excipients includeDMSO and liquids having at about 25° C. a dynamic viscosity greater thanabout 50 cP, such as greater than 100 cP, such as glycerol andpolyethylene glycols. They can optionally further include surfactants.Typically, the added excipient raises the dynamic viscosity of theformulations to above 100 cP, such as above 1000 cP, above 10,000 cP, orabove 100,000 cP at about 37° C. When dispensed through a flowrestrictor, the preferred nozzles, channels or tubes for Type Cformulations that are true solutions can have an internal diameter of 10μm-2 mm (e.g, 10 μm-100 μm, 0.1 mm-0.5 mm, or 0.5-2 mm). Although it canbe longer or shorter, the length of the flow restrictor for a Type Ctrue solution is typically 0.2 cm-10 cm.

Type D Formulations

Type D formulations include aqueous solutions, gels or suspensions ofmetal compounds, such as compounds of magnesium, zinc or iron. Their pHis typically between pH 3 and pH 10, such as between pH 4 and pH 9.Optionally, they contain a gelling agent or viscosity increasing agent,which can be a water soluble polymer, or a water-swollen polymer, suchas hyaluronic acid, polyacrylic acid, polymethacrylic acid, alginic acidor a salt of these acids. Typically, the added excipient raises thedynamic viscosity of the formulations to above 100 cP, such as above1000 cP or above 10,000 cP, above 10,000 cP, or above 100,000 cP atabout 37° C. When dispensed through a flow restrictor, the preferrednozzles, channels or tubes for Type D formulations that are truesolutions can have an internal diameter of 10 μm-2 mm (e.g, 10 μm-100μm, 0.1 mm-0.5 mm, or 0.5-2 mm). Although it can be longer or shorter,the length of the flow restrictor for a Type D true solution istypically 0.2 cm-10 cm.

Type F Formulations

Type F formulations are liquid solutions or gels including between 0.1mg/mL and 20 mg/mL of the drug. The formulations can contain water orthey can be non-aqueous (e.g., <1% water). They can include water and/oran excipient that is liquid at or below about 45° C., such as at orbelow 37° C. Examples of such excipients include DMSO and liquids havinga dynamic viscosity greater than about 50 cP (such as greater than 100cP at about 25° C.) such as glycerol and polyethylene glycols. They canoptionally further include surfactants. When water-including, they canoptionally contain a gelling agent or viscosity increasing agent, suchas a water soluble polymer or a water-swollen polymer such as hyaluronicacid, polyacrylic acid, polymethacrylic acid, alginic acid or a salt ofthese acids. Typically, the added excipient raises the dynamic viscosityof the formulations to above 100 cP, such as above 1000 cP, above 10,000cP, or above 100,000 cP at about 37° C. When dispensed through a flowrestrictor, the preferred nozzles, channels or tubes for Type Fformulations that are true solutions can have an internal diameter of 10μm-2 mm (e.g, 10 μm-100 μm, 0.1 mm-0.5 mm, or 0.5-2 mm). Although it canbe longer or shorter, the length of the flow restrictor for a Type Ftrue solution is typically 0.2 cm-10 cm.

Levodopa Formulations

LD is poorly soluble in most non-toxic solvents, including water andalcohols. For example, we have found that in a citrate buffered solutionof about pH 4.5 the solubility of LD at 25° C. is only about 0.68 g/100mL, or 34 mM. LD is even less soluble in alcohols. To deliver a typicaldaily dose of 1,000 mg approximately 150 mL of saturated LD aqueoussolution would be required, which is incompatible with the volumerequirements for a drug delivery device placed in the mouth.

DDC inhibitors such as CD are typically co-administered with LD, and itis usually desirable to co-infuse LD and CD. CD is also poorly solublein non-toxic solvents such as water, further increasing the requiredvolume of infused solution.

This invention features pharmaceutical compositions including COMTinhibitors. The exemplary COMT-inhibitor entacapone is poorly soluble inwater, is administered in large daily doses, often of greater than 1g/day, and has a physiological half-life of less than 1 hour, making itadvantageous to continuously or frequently orally co-administer it withLD or LD-CD in suspensions of this invention. It can be co-administered,for example, at a rate between 25 mg/hour and 100 mg/hour.

The invention features a pharmaceutical suspension containing a carrierand levodopa particles optionally admixed with CD (e.g., LD/CD molarratio is from about 2:1 to about 6:1, such as about 4:1). Preferredsuspensions include LD and CD. One or more additional drugs for thetreatment of Parkinson's disease may be included in the pharmaceuticalcompositions of the invention, e.g., a DDC inhibitor, a COMT inhibitor,a drug to treat gastroparesis, a MAO-B inhibitor, adenosine A2 receptorantagonists, or a dopamine agonist.

The preferred dynamic viscosities of the suspensions at about 25° C. aretypically greater than 100 cP (i.e., 1 Poise), e.g., they can be greaterthan 10, 100, 1,000, or even 10,000 Poise. Typically the more viscoussuspensions, such as suspensions having viscosities of 1,000 Poise ormore, are not pourable. While they can't be poured, they can be extrudedinto the mouth. The advantage of highly viscous, non-pourable butextrudable emulsions is that they are physically stable, meaning thatupon standing, for example for a month, 3 months, 6 months, 1 year, 2years, or longer than 2 years their suspended solid drug does notsediment. Furthermore, when the viscous suspensions include an emulsion,their aqueous and organic or oil phases may not separate. Anotheradvantage of the viscous suspensions is that the oxidation of theirdrugs by dissolved oxygen, the rate of which can be diffusion andtherefore viscosity-dependent, is greatly slowed. While air-exposedsolutions of LD or CD can turn dark, even black, in one day because ofair oxidation, the suspensions remain off-white when air-exposed for amonth. At the high viscosity also the rate of O₂-oxidation of CD wherebytoxic hydrazine is produced is reduced, greatly increasing the shelflife, which can be at the typical ambient temperature of 25° C.±3° C.longer than 3 months, such as longer than 6 months, or even longer than1 year, in which the hydrazine can be less than 8 μg (e.g., 7 μg, 6 μg,5 μg, 4 μg, 3 μg, 2 μg, or 1 μg) per mg of carbidopa.

Other than the exemplary emulsion-including suspensions of the soliddrugs, viscous suspensions of solid drugs could be made with thickeners,such as carboxymethylcellulose. Concentrated sugar solutions, such assucrose solutions, are also viscous. For example, the solid drugs may besuspended in a sugar (e.g., sucrose, dextrose, glucose) solutioncontaining 40%-70% sugar by weight, e.g., 40%-50% sugar by weight,50%-60% sugar by weight, or 60%-70% sugar by weight. As previouslydiscussed, the LD and CD formulations may include multimodal particlesize distributions.

The pH of the formulations including those of the emulsion including LDand/or CD suspensions can be between 2.5 and 9.5, the more acidicsolutions damaging the enamel of teeth and the more basic solutionshaving bad taste. The pH range between about 3 and 7.5 is preferred andthe range between 3 and 5 is most preferred, because of slowerair-oxidation of LD and CD, resulting in the case of CD also in a lesserrate of formation of toxic hydrazine and consequently in a longer shelflife when the shelf life is limited by the hydrazine content, as it isin the jejunally infused Duodopa™.

The LD/CD including pharmaceutical compositions can have an apparent pH(meaning a pH measured by inserting a glass walled pH electrode into thecomposition) of more than pH 2 but less than pH 5 (e.g., less than pH 4,less than pH 3.5, between about pH 2.7 and about pH 3.3, or about pH 3)and it can remain less than pH 5 (e.g., less than pH 4, less than pH3.5, or about pH 3) after 3 months storage at 25±3° C. The compositionscan include a bacteriostatic and/or a fungistatic agent, such as benzoicacid or a benzoate salt. The combined concentrations of benzoic acid andbenzoate salt such as its sodium salt is between 0.1 weight % and 1.0weight % (such as between 0.2 weight % and 0.6 weight %) of thepharmaceutical composition and can optionally include more benzoic acidthan benzoate salt, e.g. sodium benzoate. The compositions can alsoinclude a transition metal ion complexing agent such as EDTA and/or itssalts, such as its sodium salts. The concentration of the EDTA and itssalts (e.g. sodium salts) is between 0.05 weight % and 0.25 weight % ofthe pharmaceutical composition. The pharmaceutical composition mayinclude a sulfur-including compound, such as a thiol reacting at 25±3°C. with dopaquinone or with the quinone formed by oxidation ofcarbidopa, exemplified by cysteine or N-acetylcysteine.

In general, the color of the emulsion-based suspensions of LD and CDwhen exposed to air at ambient temperature (about 25° C.) remainsoff-white for at least one week, e.g., 2 weeks or more or 1 month ormore.

The densities of the emulsion-including suspensions in the absence oftrapped air can be between about 1.15 g/cm³ and about 1.3 g/cm³, such asbetween about 1.20 g/cm³ and 1.27 g/cm³. Most of the trapped air can beremoved by centrifugation.

Method of Preparing the Concentrated Formulations of the Invention

The invention also features a method of preparing the pharmaceuticalcomposition of the invention. The method can involve contacting (e.g.,mixing) solid particles of the drug with an aqueous solution containinga surfactant and water, whereby a mixture of the solid particles withthe aqueous surfactant solution is produced, followed by mixing with anoil. Pharmaceutical compositions that can be prepared according to thismethod are described herein.

Control of Hydrazine Formation

Stored CD is known to degrade such that hydrazine is produced. In animalstudies, hydrazine shows notable systemic toxicity, particularly uponinhalation. Hydrazine is also hepatotoxic, has CNS toxicities (althoughnot described after oral treatment), and is genotoxic as well ascarcinogenic. Consequently, it is important to minimize hydrazineformation during storage of CD or LD/CD formulations.

Duodopa™, a LD/CD suspension for continuous intraduodenal infusion,produces hydrazine during storage. The average recommended daily dose ofDuodopa is 100 mL, containing 2 g levodopa and 0.5 g CD. The maximumrecommended daily dose is 200 mL. This includes hydrazine at up to anaverage exposure of 4 mg/day, with a maximum of 8 mg/day. In order tomeet these exposure limits, Duodopa's labeling (outside the USA) statesthat its refrigerated, unopened shelf life is just 15 weeks, and thatonce removed from the refrigerator and opened the product may only beused for up to 16 hours. In the United States, Duodopa (sold in the USAas Duopa) requires frozen storage and its labeled shelf life is 12 weeksrefrigerated (after thawing). The concentrations of LD and CD in Duodopaare 20 mg/mL and 5 mg/mL, respectively.

A stable fluid formulation of CD that does not contain high levels ofhydrazine and that can be stored unrefrigerated for extended periods oftime is desirable. Hydrazine is produced almost entirely by oxidation ofCD in solution; as more of the dissolved CD is degraded over time, moreof the suspended CD is dissolved and is itself degraded. In this waysignificant amounts of hydrazine can accumulate over time. Hydrazine isnot produced in significant quantities by oxidation of suspended CDparticles. Therefore, the amount of hydrazine produced is greatlyreduced by simultaneously minimizing the amount of aqueous ornon-aqueous liquid in which the hydrazine can dissolve, and maximizingthe concentration of the suspended solid CD. Such an approach maximizesthe ratio of the suspended solid CD to the dissolved CD. The inventionfeatures an oral liquid impermeable reservoir containing a suspension ofCD in a fluid volume of 0.20-5.0 mL, wherein the concentration of solidCD suspended in the fluid is 50-500 mg/mL. The invention features a CDsuspension containing less than about 4 mg, 1 mg, or 0.25 mg ofhydrazine per 500 mg of CD after storage of the suspension at 5±3° C.for 1 year, or at 25±3° C. for 3 months, 6 months, 12 months, or 24months. Preferred reservoirs are substantially free of oxygen and aresubstantially impermeable to oxygen. Preferably, LD is also present inthe drug reservoir. Preferrably the drug is formulated with a carrier(e.g., an emulsion) in which CD has a very low solubility, such aswater-oil emulsion. Because of the poor solubility of CD in the carrierused in the suspensions of the invention, most of the CD is in thesolid, particulate form. Because hydrazine is formed mostly orexclusively of dissolved CD, not of solid particulate CD, thedecomposition of CD, with concomitant formation of hydrazine, isminimized.

To further reduce the formation of hydrazine, the CD-includingpharmaceutical compositions can have an apparent pH (meaning a pHmeasured by inserting a glass walled pH electrode into the composition)of more than pH 2 but less than pH 5 (e.g., less than pH 4, less than pH3.5, between about pH 2.7 and about pH 3.3, or about pH 3) and it canremain less than pH 5 (e.g., less than pH 4, less than pH 3.5, or aboutpH 3) after 3 months storage at 25±3° C. The compositions can alsoinclude a transition metal ion complexing agent such as EDTA and/or itssalts, such as its sodium salts. The concentration of the EDTA and itssalts (e.g. sodium salts) is between 0.05 weight % and 0.25 weight % ofthe pharmaceutical composition. The pharmaceutical composition mayinclude a sulfur-including compound, such as a thiol reacting at 25±3°C. with dopaquinone or with the quinone formed by oxidation ofcarbidopa, exemplified by cysteine or N-acetylcysteine.

Pump-Driven Suspension Separation

The inventors observed that some suspensions with high solid drugconcentrations maintain their uniformity of composition, i.e., may notshow sedimentation upon storage at about 25° C., for at least two days,yet when a flow-causing pressure is applied the suspensions can becomenon-uniform. The invention includes compositions and methods forpreventing pressure-induced separation of pumped, viscous suspensions.When viscous suspensions are pumped under pressure, separation of thesolids from the liquid carrier is often observed. Typically, the pumpdelivers a fluid that contains a reduced amount of solids and the solidsaccumulate behind the orifice and are not delivered to the patient. Inpreferred embodiments, the drug delivery devices of the inventioninclude one or more suspension flow-enhancement elements thatsubstantially prevent pressure-induced separation of pumped, viscoussuspensions.

For example, this phenomenon was observed during an experiment todeliver a suspension of LD and water with a viscosity of approximately50,000 cP. The driving pressure was approximately 41 inches H₂O througha nozzle with an inner diameter of 0.603 mm. The suspension separatedand a murky fluid dripped from the end of the nozzle. As the pressurewas increased to 60 and then 80 in H₂O, the separation persisted, withincreasing clarity of the exuding fluid. As the pressure was decreasedby increasing the nozzle diameter, the effect was lessened, but was noteliminated.

This and other experiments showed that pressure induced flow can causeformation of a filtering plug, the plug passing more of the carrierfluid and less of the solid drug. Such pressure or flow-inducedsedimentation, i.e., filtering-plug formation, makes it difficult, ifnot impossible, to maintain a fixed dose rate by controlling the flow.Sedimentation leading to filtering may be alleviated when the suspendedparticle sizes are bimodally or multimodally distributed. Suspensionswith multimodal particle size distributions tend to have superior flowcharacteristics over particles with unimodal particle sizedistributions, thereby reducing or eliminating the of separation orsedimentation of the solids from the liquid carrier that can occur whena suspension is pumped. Filtering could be reduced or avoided byincreasing, through the bimodally or multimodally distributed particlesizes, the volume fraction, i.e., packing density, of the suspendedsolid drug, typically to greater than about 0.64, for example to between0.65 and 0.69. A two-dimensional example of an optimal trimodaldistribution of particle sizes is illustrated in FIG. 20. The largestparticle 86 is shown packed with a second smaller particle 87 and afurther smaller third particle size 88. Particle 88 is approximately⅕^(th) the diameter of 87 and particle 87 is approximately ⅕^(th) thediameter of the particle 86.

The invention includes suspensions for infusion into the mouth includingbimodal or multimodal particle size distributions, optionally whereinthe ratio of the average particle diameters for the peaks is in therange of 2:1 to 7:1, e.g., about 3:1, 4:1, 5:1, 6:1, or 7:1. In thebimodal or multimodal distributions particle sizes can peak, forexample, between 0.5 μm and 100 μm, such as between 1 μm and 50 μm, orbetween 1 μm and 30 μm, or between 1 μm and 15 μm. In general, proximalparticle sizes at the maxima of the bimodal or multimodal distributiondiffer twofold or more, for example between two and fourfold, or betweenfour and six-fold. In an exemplary bimodal distribution the weight-basedamount of the larger particles can equal or be greater than that of thesmaller particles. Typically the large particle: small particle weightratio is typically greater than 1; it can be, for example, between 1 and2, such as between 1.2 and 1.8, such as about 1.5.

The invention includes reduction or elimination of pump-drivensuspension separation in the intra-oral drug delivery devices by use ofone or more of the following suspension flow enhancement elements:

-   -   Formulation of pumped suspensions with multimodal particle size        distributions that increase the volume fraction of solids. As        previously described, the invention includes suspensions for        infusion into the mouth including multimodal particle size        distributions, preferably wherein the ratio of the volume        weighted average particle diameters at the peaks is in the range        of 1.5:1 to 7:1, such as between 3:1 to 7:1.    -   Use of surfactants that facilitate the extrusion of the        particle-including suspensions through the orifice or tube,        exemplified by surfactants used as food additives, such as        monoesters of glycerol and fatty acids like glyceryl monooleate        or glyceryl monostearate, or a polysorbate like Polysorbate 80,        65, 60 or 20, or a Kolliphor™ such Kolliphor RH 40, or a        Poloxamer such as Poloxamer 188.    -   Use of coatings that modify the surface of the orifice or tube,        facilitating the extrusion of the particle-rich suspension        through the orifice or tube, such as a fatty acids, or coating        the orifice with a perfluorinated polymer, exemplified by        Teflon™ or its lubrication with a fluorinated hydrocarbon like        Kryton™ or fluorinated polyether such a Fomblin™. Alternatively,        the orifice or tube can be made of a fluorinated polymer, such        as a perfluorinated polymer.    -   Flaring of the orifice to enhance the flow of particles through        the orifice or tube.    -   Use of an orifice inner diameter of at least 5, 10, or        preferably 20 times the maximum particle size (i.e., the D₉₀,        D₉₅, or D₉₈).    -   Selection of a formulation viscosity, concentration, and flow        rate, and an orifice inner diameter, such that the pressure on        the suspension is less than 10 bars, and preferably less than 5        bars.

The invention features combinations of these designs and methods suchthat the drug concentration in the suspension delivered by the drugdelivery device varies by less than 20%, 10%, 5%, and preferably 3% fromthe average during each one hour interval over a period of 8, 16, or 24hours.

Oral Liquid Impermeable Drug Reservoirs

The preferred drug reservoirs of the invention are oral liquidimpermeable reservoirs. For such oral liquid impermeable drugreservoirs, 1, 4, 8, 16, 24, 48, or 72 hours after placing a drugdelivery device including a fresh reservoir in a patient's mouth andinitiating the administration, less than 5%, 3%, or 1% by weight of thedrug-including solid or drug-including fluid in the reservoir includesan oral liquid (e.g., less than 1% after 1 hour, less than 1% after 24hours, less than 3% after 8 hours, less than 5% after 4 hours, or lessthan 5% after 72 hours). The oral liquid impermeable reservoirs maycontain one or more drugs in solid form or in fluid form. Oral liquidsinclude any fluid originating from the mouth, including saliva (or itswater component) and other fluids commonly found in the mouth or thatare commonly drunk or consumed by the patient, including diluted oilsand alcohols. Exemplary oral liquid impermeable reservoirs can be madeof a metal, or a plastic that can be elastomeric or fiber-reinforced.Metallic reservoirs can include, for example aluminum, magnesium,titanium or iron alloys of these. When made of a plastic it can have ametallic barrier layer; or a non-metallized plastic or elastomer usedfor packaging of food, or for drink-containing bottles, or in a fabricof washable clothing (e.g., Nylon or Dacron), or in stoppers or seals ofdrink containing bottles, or in septums of vials containing solutions ofdrugs. Ingress of oral liquids into openings in the reservoir can beprevented or minimized by the use of one or more valves, squeegees,baffles, rotating augers, rotating drums, propellants, pneumatic pumps,diaphragm pumps, hydrophobic materials, and/or hydrophobic fluids. Insome embodiments, multiple doses of fluid or solid drug are containedwithin multiple, impermeable reservoirs or compartments.

While the extrusion into the mouth of a highly viscous plugsubstantially decreases the potential for saliva ingress, other methodsthat substantially prevent the ingress of saliva can be utilized. Salivaingress could result of capillary climb, associated with wetting of theinner surface of the drug delivering tube or orifice by saliva.Capillary climb occurs when the adhesive forces between the surface ofthe tubing and the saliva are stronger than the cohesive forces (surfacetension) of the saliva. One method to reduce or eliminate capillaryclimb is to reduce the cohesive forces by utilizing a large diametertubing between the drug reservoir and the exit orifice. Another methodto eliminate capillary climb is to reduce the adhesive force of thesurface of the tubing through the use of a hydrophobic coating on theinner surface of the tubing. The goal of the coating is to preventwetting of the tubing. By diminishing the released surface energy of thetubing upon wetting by saliva (e.g., by making it of, or by its coatingwith, a difficult to wet perfluorocarbon like Teflon™, or itslubrication by a difficult to wet fluorinated hydrocarbon like Kryton™,or by a difficult to wet fluorinated polyether like a Fomblin™) agreater than 90 degree contact angle between the saliva and the innersurface of the tubing can be achieved and capillary climb can be reducedor prevented. Another method to limit ingress of saliva is the use of acheck valve 16 (illustrated in FIGS. 15A and 15B). In times where theflow is halted or paused, the pressure gradient across the check valve16 is eliminated, closing the valve and preventing the flow of drug andthe ingress of saliva.

For ergonomic reasons, the drug reservoirs and/or devices of theinvention may include syringes, barrels and plungers that are not thecustomary cylindrical shapes. An example of an alternative shape for thedrug reservoir (e.g., a syringe and plunger) is an obround shape.Alternatively, a non-cylindrical (e.g., obround) housing may include twoor more cylindrically shaped syringes, barrels and/or plungers arrangedside-by-side.

A drug reservoir used in the drug delivery device of the invention canbe a syringe assembly including a plunger and a barrel, where theplunger is in a slidable arrangement with the barrel. Administration ofa drug from the drug reservoir can involve relative, slidabledisplacement of the barrel and the plunger by a drug pump (e.g., amechanical pump, such as a spring-driven drug pump or apropellant-driven pump), such that the volume enclosed by the barrel andthe plunger is decreased. The syringe assembly may include a seal fittedover the plunger, the seal being in contact with the barrel to seal theinterface between the barrel and the plunger. The seal can be an O-ring.To reduce variability in drug delivery due to friction or stickiness ofthe syringe, some or all of the interior surfaces of the syringe (e.g.,the barrel, the plunger, or the seal) may include a non-stick coatingsuch as a fluorinated polymer, e.g., Teflon™ or a fluorinated polymerlike Kryton™ or Fomblin™. The interior surfaces can be non-wettable byoil or by water (e.g., by the preferred pharmaceutical composition ofthe invention, which is typically an emulsion including a suspension ofsolid particles).

In some embodiments, the drug delivery device can include a tapered flowpath for the pharmaceutical composition as it approaches the flowrestrictor, exit orifice, or tube. The taper can make the flow of thepharmaceutical composition more reproducible. FIG. 22 illustrates a drugreservoir 4 in the shape of a syringe barrel with a tapered flow path atthe exit orifice 75. The angle of the taper, α, can be equal to or lessthan about 60 degrees, 45 degrees, or 30 degrees.

To achieve reproducible and accurate drug delivery, it is preferred thatthe components of the syringe be made of materials that do notsubstantially deform, e.g. creep or yield, under the stress resulting ofthe force exerted to deliver the drug. It is also preferred that thecomponents of the syringe have matched or similar thermal expansioncharacteristics so that the friction between the barrel and the pistonor seal remains about constant as the temperature varies, and so thatthere is minimal leakage of the drug suspension during storage. This canbe accomplished, for example, by using barrels, plungers and/or sealswith glass transition temperatures of greater than 37° C., preferablygreater than 45° C., more preferably greater than 60° C., and mostpreferably greater than 90° C.; and by using syringe components madefrom the same material so that they have the same thermal expansioncoefficients. Examples of such materials are polycarbonate, polystyrene,non-creeping perfluorinated polymers, polyamides like Nylon 6-6,polymethylmethacrylate, and PET. Materials such as polypropylene areless desirable due to their low glass transition temperature andconsequent easy deformation at 37° C.

Alternatively, the moving surface and the nearby stationary surface(e.g., the inner surface of a syringe barrel) can be rendered non-stickyby a lubricant. As the lubricant may come in contact with thepharmaceutical composition of the invention inside the drug deliverydevice of the invention, the lubricant should exhibit low or nosolubility in the pharmaceutical composition of the invention. In someembodiments, the lubricant has an oil solubility less than 3% (w/w) atabout 25° C. (e.g., less than 2% (w/w) at about 25° C., less than 1%(w/w) at about 25° C., or less than 0.5% (w/w) at about 25° C.). Inother embodiments, the lubricant has aqueous solubility less than 2%(w/w) at about 25° C. (e.g., less than 1% (w/w) at about 25° C., lessthan 0.5% (w/w) at about 25° C., or less than 0.2% (w/w) at about 25°C.). The lubricant can be a halogenated polymeric oil (e.g., ahalogenated polymeric oil having an average molecular mass of equal toor greater than about 1,000 Daltons, or having an average molecular massof equal to or greater than about 2,000 Daltons). Certain lubricants canbe a perfluorinated polymer, a chlorofluorinated polymer, or afluorinated polyether.

In another embodiment, the lubricant includes two organic fluid phases,such as two organic immiscible phases. These phases may be pourable ornon-pourable. An example is lubricant including both a silicone oil orgrease and a fluorinated polyether oil or grease. Another example is alubricant including both hydrocarbon oil or grease and a fluorinatedpolyether oil or grease.

In yet another embodiment, the compartment including the driving element(e.g., the propellant or spring) may be separated from the compartmentincluding the drug suspension (e.g., LD and CD suspension in a syringebarrel) by a plug of material. The plug replaces a solid plunger andprovides reduced friction and more reproducible drug delivery. The plugmay be deformable and/or mobile, and may optionally be non-pourable. Thepressure of the propellant causes the plug to move and/or deform, andtransmits the pressure to the suspension. Use of a non-pourable plugserves to keep the propellant and the suspension separate by preventingpenetration of the propellant gas into the drug, assuring that thesuspension, and not the gas, is delivered to the patient. Preferably therate of permeation of the components of the drug suspension in the plug,and optionally also of the propellant in the plug, is low. The rate ofpermeation of water through the plug can be, for example, less thanabout 10 mg per day at about 25±2° C., for example less than 1 mg perday or less than 0.1 mg per day. Similarly, the rate of permeation ofoil through the plug can be, for example, less than about 10 mg per dayat about 25±2° C., for example less than 1 mg per day or less than 0.1mg per day. Furthermore, the rate of permeation of the optionally usedpropellant, used to drive the plug, can be less than about 1 mg per dayat about 25±2° C., for example less than about 1 mg per day or less thanabout 0.1 mg per day, or less than about 0.01 mg per day. Exemplary plugmaterials in which the solubilities of water and/or oil and/orpropellant are low include perfluorinated or fluorinated orchlorofluorinated oils and greases. The oils and greases may includesolid and preferably inorganic particles to reduce their permeabilities,such as particles of carbon, silica, alumina, titania, or halogenated,particularly fluorinated, solid polymer particles, exemplified bypolytetrafluoroethylene particles. The carbon particles can be, forexample, particles of graphite, such as graphite flakes. The solidparticles may have densities between about 1.5 g/mL and about 3 g/mL,for example between about 1.6 g/mL and about 2.5 g/mL, such as between1.6 g/mL and 2.1 g/mL. The average or mean size of these particles inthe grease can be between about 0.5 μm and about 250 μm, for examplebetween about 1 μm and about 100 μm. Typically, the incorporated solidparticles scatter and/or absorb visible light. Exemplary oils andgreases may include fluorinated polyethers or polymeric fluorinatedalkanes such as perfluoroalkanes. Some fluorinated polyether oils andgreases are sold under the trade name “Fomblin™” and some fluorinatedhydrocarbon oils and greases are sold under the trade name “Krytox™”.The oil or grease may wet the walls of the compartment or may not berepelled from the walls, as indicated, for example, by a concavemeniscus or no meniscus when the oil is in an optionally cylindricalcompartment, and the absence of a convex meniscus when the oil is in anoptionally cylindrical compartment. Optionally, the plug may include oneor more solid supports to provide the plug with greater structuralintegrity, to further reduce the rate of permeation of gasses or drugthrough the plug, and to reduce leaching of materials from the plug intothe drug or into the propellant. For example, the plug may include ametal or polymeric mesh or cage, or a metal or polymeric cap on one orboth ends.

Methods of Use and Methods of Treating Disease

The drug delivery devices of the invention can be used to orallyadminister drugs to patients in therapeutically effective amounts.Similarly, the formulations of the invention can be administered topatients in therapeutically effective amounts. For example, an amount isadministered which prevents, delays, reduces, or eliminates the symptomsof a disease, such as PD, mucositis, bacterial infections, cancer, pain,organ transplantation, disordered sleep, epilepsy and seizures, anxiety,mood disorders, post-traumatic stress disorder, cancer, arrhythmia,hypertension, heart failure, spasticity, diabetic nephropathy, andallergy. They can also be used to manage allergies, e.g. by deliveringagents used for sublingual immunotherapy such that the delivered agentscontact a mucous membrane or tissue of the mouth. Using the drugdelivery devices of the invention, a drug appropriate for the treatmentof a given disease to be treated can be formulated and administeredusing the methods, compositions, and devices described herein.

Many drugs with narrow therapeutic indices benefit from drug deliverydevices and methods that result in small fluctuation indices. Forexample, Table 2 summarizes the fluctuation indices of extended releasetablet formulations of anti-epileptic drugs reported in various studies(from “Extended-release antiepileptic drugs: A comparison ofpharmacokinetic parameters relative to original immediate-releaseformulations”, Ilo E. Leppik and Collin A. Hovinga, Epilepsia,54(1):28-35, 2013).

TABLE 2 Fluctuation indices of anti-epileptic drug extended releasetablets. Drug Fluctuation Index (SD) Carbamazepine 0.31 (0.1) 0.26 (0.1)0.47  0.49  Divalproate sodium 0.39 (0.15) 0.67 (0.16) 0.34 (0.15) 0.67(0.17) 0.59 (0.27) 0.46 (0.16) 0.71 (0.20) Lamotrigine 0.341 0.817 0.2090.545 0.986 0.318 Oxcarbazepine 0.39 (0.08) 0.54 (0.09) Levetiracetam1.19  1.27 

The invention includes a method of treating a disease or medicalcondition using any of the devices, drugs, formulations, and methodsdisclosed herein, wherein the fluctuation index is less than or equal to2.0, 1.5, 1.0, 0.75, 0.50, 0.25, or 0.15. For example, the disease ormedical condition to be treated may be Parkinson's disease, bacterialinfections, cancer, pain, organ transplantation, disordered sleep,epilepsy and seizures, anxiety, mood disorders, post-traumatic stressdisorder, cancer, arrhythmia, hypertension, heart failure, spasticity,dementia, diabetic nephropathy, gastroparesis, xerostomia, and dementia.

Drug dosages administered using the methods of the invention may behigher or lower than those administered using traditional, infrequentdosing regimens. A lower daily dose is possible without loss of efficacywhen continuous or semi-continuous administration reduces troughs in thedrug's steady state circulating plasma concentration, enabling thedrug's plasma concentration to remain above the minimum effective plasmaconcentration without the need for high peak concentrations. A higherdaily dose is possible without increased side effects when continuous orsemi-continuous administration reduces peaks in the drug's steady statecirculating plasma concentration, enabling an increase in the drug'saverage plasma concentration without the need for high peakconcentrations.

The methods of the invention provide a dosing regimen having an improvedsafety profile as adverse events associated with peak plasmaconcentrations (i.e., a C_(max) characteristic of oral unit dosageforms) are eliminated. Thus, the methods, compositions, and devices ofthe invention can be used to deliver drugs having a narrow therapeuticwindow in the patient population being treated (i.e., patientsrefractory to standard therapeutic regimens). Details provided below forthe treatment of PD can be applicable to the formulation andadministration of drugs for the treatment of other diseases.

Treatment of PD

For the treatment of PD, typical administered dose ranges are from about20 μmole/kg to about 200 μmole/kg of LD or LD prodrug per day. Thetypical daily dose of the optionally co-administered DDC inhibitor isbetween about 5 μmole/kg and about 50 μmole/kg. For example, the typicaldaily dose for a patient weighing 75 kg is from about 1.5 millimoles toabout 15 millimoles of LD or LD prodrug. Optionally, a molar amount of aDDC inhibitor between about 10% and about 40% of the molar amount of theLD or LD prodrug, for example between 15% and 30%, may be added.

Preferred modes of administration of the drug-including solid or fluidare via drug delivery devices that are removably secured in the mouth,and which administer the drug into the mouth or into the nasal cavityfor a period of at least 4 hours. The drug may be administered at avariable rate, although constant rate administration is preferred.Administration is preferably continuous or semi-continuous.

The administration into the mouth can be for 24 hours daily or it can belimited to the awake period, typically about 16 hours. When limited tothe awake period it can be advantageous to administer a morning bolus tomore rapidly raise the plasma concentration of the LD than a constantrate administration would. The morning bolus can be delivered, forexample, through an orally taken pill or pills of LD and a DDC inhibitoror it can be through administration of a solid or fluid drug into themouth using the drug devices of the invention. Alternatively, theexterior of the drug delivery device may include a drug, such that abolus of the drug is delivered into the mouth when the device is firstinserted into the mouth.

The invention includes methods of administering into the mouth one ormore drugs (e.g., LD and CD) from one or more drug reservoirs residingin the cavity of the mouth including a total volume of 0.1-10 mL ofdrugs (e.g., 0.1-1.0 mL, 1.0-2.0 mL, 2.0-3.0 mL, 3.0-4.0 mL, 4.0-5.0 mL,5.0-6.0 mL, 6.0-7.0 mL, 7.0-8.0 mL, 8.0-9.0 mL, or 9.0-10 mL). Theinvention includes methods of administering the one or more drugs (ineither solid or fluid form) at a rate in the range of 0.03-1.25 mL/hour(e.g., 0.03-0.10 mL/hour, 0.10-0.20 mL/hour, 0.20-0.30 mL/hour,0.30-0.40 mL/hour, 0.40-0.50 mL/hour, 0.50-0.60 mL/hour, 0.60-0.70mL/hour, 0.70-0.80 mL/hour, 0.80-0.90 mL/hour, 0.90-1.0 mL/hour, 1.0-1.1mL/hour, or 1.1-1.25 mL/hour). The invention includes methods ofadministering the one or more drugs at an average rate of less than 1 mgper hour, 1-10 mg per hour, 10-25 mg per hour, 25-50 mg per hour, 50-75mg per hour, 75-100 mg per hour, 100-125 mg per hour, or greater than125 mg per hour. The invention includes methods of administering one ormore drugs via continuous and/or semi-continuous administration. In apreferred embodiment, the method includes holding the averageadministration rate constant or near constant for a period of 4, 8, 12,16, or 24 hours during the day. For example, the volume administeredevery hour may vary from the average hourly administration rate duringthe infusion period by less than ±10% or ±20% per hour, or by ±10% or±20% per 15 minute period. The invention includes methods ofadministering one or more drugs into the mouth using any of the drugdelivery devices described herein.

Continuous or semi-continuous administration using the drug deliverydevices and formulations of the invention can reduce concentrationfluctuations of the therapeutic drug in body fluid, for example inblood, plasma or serum. It can provide, for example, a plasmaconcentration profile where the difference between peak concentrationsand nadir concentrations of the therapeutic drug is less than ±70% ofthe average concentration through a period in which the drug isadministered, for example it can be less than ±50%, less than ±30%, lessthan ±20%, or less than ±10% of the time averaged concentration over aperiod of greater than or equal to 4 hours (e.g., 8, 12, 16, or 24hours).

The invention features a method of treating a disease in a patient, themethod including: (a) inserting a drug delivery device into thepatient's mouth; (b) starting a drug administration from the device; (c)administering into the patient's mouth one or more drugs, usingcontinuous or semi-continuous administration, for a period of 4 hours to7 days at an hourly rate in the range of 0.015-1.25 mL/hour or 1-125mg/hour; and (d) removing the drug delivery device from the mouth;wherein the drug delivery device includes a oral liquid impermeablereservoir of 0.1-5 mL volume (e.g., 0.1-1 mL, 0.5-3 mL, or 3-5 mL), andthe reservoir includes a solid or fluid including a drug. Optionally,the method may also include the optional step of: (e) stopping the drugdelivery from the device. The invention further includes a methodwherein steps a, b, c, d and e are performed at least twice over aperiod of 4 hours to 7 days. The drug may include a total of greaterthan 1 millimole of LD.

The invention features a method of treating a disease in a patient, themethod including: (a) inserting a drug delivery device into thepatient's mouth; (b) starting a drug administration from the device; (c)administering into the patient's mouth one or more drugs, usingcontinuous or semi-continuous administration, for a period of 4 hours to7 days at an hourly rate in the range of 0.015-1.25 mL/hour or 1-125mg/hour; (d) removing the drug delivery device from the mouth; and (e)stopping the drug delivery from the device, wherein: (1) the drugdelivery device includes a reservoir of 0.1-5 mL volume (e.g., 0.1-1 mL,0.5-3 mL, or 3-5 mL), and the reservoir includes a solid or fluidincluding a drug, and (2) steps a, b, c, d and e are performed at leasttwice over a period of 4 hours to 7 days. The drug may include a totalof greater than 1 millimole of LD.

The invention features a method for treating Parkinson's disease in apatient (including in patients with scores of 4 and 5 on the Hoehn andYahr scale), the method including: (a) removably inserting a drugdelivery device into the patient's mouth, the drug delivery deviceincluding an oral liquid impermeable reservoir of 0.1-5 mL volume (e.g.,0.1-1 mL, 0.5-3 mL, or 3-5 mL), and the reservoir including a solid orfluid including a total of greater than 1 millimole of LD; (b)administering into the patient's mouth the solid or fluid for a periodof at least 8 hours at an hourly rate in the range of 0.03-1.25 mL/houror 30-150 mg/hour, such that a circulating plasma LD concentrationgreater than 400 ng/mL and less than 7,500 ng/mL is continuouslymaintained for a period of at least 8 hours during the administration;and (c) removing the drug delivery device from the patient's mouth. Incertain embodiments, the LD suspension is administered into the mouth atsuch a rate that a circulating plasma LD concentration greater than 800ng/mL, 1,200 ng/mL, 1,600 ng/mL, or 2,000 ng/mL (e.g., from 800 to1,500, from 1,000 to 2,000, from 1,600 to 2,500, or from 1,500 to 3,000ng/mL, depending upon the condition of the patient) is continuouslymaintained for a period of at least 2 hours, 3 hours, 4 hours, 8 hours,16 hours, or 24 hours during the administration. In particularembodiments, the LD suspension is administered into the mouth at such arate that a circulating plasma LD concentration greater than 400 ng/mL,800 ng/mL, 1,200 ng/mL, 1,600 ng/mL, or 2,000 is achieved within 60minutes of the initiation of the infusion. The LD suspension can beadministered into the mouth at such a rate that a circulating plasma LDconcentration less than 7,500 ng/mL, 5,000 ng/mL, 3,500 ng/mL, 3,000ng/mL, 2,500 ng/mL, or 2,000 ng/mL is continuously maintained for aperiod of at least 8 hours during the administration. In particularembodiments, the patient receives an average daily dose of less than 10mL, 7.5 mL, 5 mL, 3 mL, or 2 mL of the LD suspension. The LD suspensioncan be administered into the mouth at such a rate that the circulatingLD plasma concentration varies by less than ±20%, ±15%, or ±10% from itsmean for a period of at least 1 hour, 2 hours, 3 hours, or 4 hours.

The method can further include the co-administration of an effectiveamount of a DDC inhibitor such as benserazide, carbidopa or carbidopaprodrug. Carbidopa can be co-administered as a solid, suspension oremulsion, or as a solution of one of its highly water soluble prodrugsalts, exemplified by carbidopa ethyl ester hydrochloride, by carbidopamethyl ester hydrochloride or by carbidopa amide hydrochloride. Themolar amount of the co-administered DDC inhibitor can be betweenone-tenth and one-half of the molar amount of LD, preferably about¼^(th)±⅛^(th) of the molar amount of LD. Preparations of the carbidopaprodrugs, recognized to be LD decarboxylase inhibitors, are described,for example, in U.S. Pat. Nos. 3,895,052 and 7,101,912, and PatentPublication Nos. DE2062285A and FR2052983A1. In one particularembodiment, a LD suspension includes a greater than 0.5 M LD (e.g.,0.5±0.1, 0.6±0.1, 0.7±0.1, 0.8±0.2, 1.0±0.3, 1.5±0.5, 2.0±0.5, 0.6±0.3,0.75±0.25, 1.0±0.5, 1.5±0.5, 2.0±0.5, 2.5±0.5, 3.0±0.5, 3.5±0.5, greaterthan 1.5, greater than 2, greater than 2.5, or greater than 3.5 molesper liter). In particular embodiments, the LD and the DDC inhibitor areco-administered separately, or are contained in a single solid or fluidand administered into the patient.

The method can alleviate a motor or non-motor complication in a patientafflicted with Parkinson's disease, such as tremor, akinesia,bradykinesia, dyskinesia, dystonia, cognitive impairment, and disorderedsleep.

Mucosal Delivery

In some embodiments, e.g. those where the daily dose of the drug is lessthan 100 mg, for example less than 50 mg, a part or most of the drug inthe continuously pumped composition can be transported into, i.e.absorbed by, the buccal or sublingual mucosa and optionally through themucosa to the blood. It could reach through venules the facial vein,then the jugular vein and the heart, delivering part of thedrug-including blood to the brain, the lungs or other organs, withoutthe drug-containing blood passing the liver or the kidneys where thedrug could be eliminated. Transport of the drug to and/or through themucosa can be enhanced by additives and or physical means described, forexample, in “Enhancing the Buccal Mucosal Delivery of Peptide andProtein Therapeutics” Pharm Res (2015) 32: 1-21 by T. Caon, L. Jin, C.M. O. Simöes, R. C. Norton and/or J. A. Nicolazzo; and/or “Mucoadhesivepolymers for buccal drug delivery.” Drug Dev Ind Pharm. (2014)40(5):591-8 by F. Laffleur, both incorporated herein by reference.Typically the composition is pumped within a zone from which more thanabout one half of the drug is transported to the mucosa in less thanabout 60 minutes, such as less than 30 minutes, 10 minutes, 5 minutes,or 2 minutes.

The invention further includes delivering the drug-containingcomposition into a location in the mouth such that the drug has aresidence time at or near the mucosa of greater than 2 minutes, 5minutes, 10 minutes, 30 minutes, or 60 minutes before being removed fromcontact with the oral mucosa (e.g., by substantial saliva-dilutionfollowed by swallowing). Several techniques and device configurationsmay be used to obtain the desired residence time, optionally incombination with each other. In one embodiment, the drug-containingcomposition is delivered into a portion of the mouth where the flux ofsaliva is slow, e.g., into the cheek pocket between the bottomteeth/gums and the cheek, and preferably not proximate a salivary gland.In a related embodiment, the composition may be mucoadhesive or includea mucoadhesive to retain the drug proximate the mucosa. In yet anotherrelated embodiment, the drug-containing composition may be deliveredinto a material that retains the drug proximate the mucosa, such as asorbent.

The accuracy and repeatability of dosing of the drug into the buccal orsublingual mucosa can be enhanced by locating the distal end of thecomposition-delivering e.g. plastic tubing or metallic pipe proximal tothe buccal or sublingual mucosa within a zone bounded in part by a watervapor and gas permeable membrane that is not saliva-wetted i.e. issaliva-repelling. The saliva-repelling gas permeable membrane can delaydilution or extraction of the pumped composition by saliva, keeping itnear the mucosa until the uptake of its drug by the mucosa. The membranecan include fibers coated with a fluorinated polymer, or its fibers caninclude, e.g. be made of, a fluorinated polymer. Exemplary waterproof,breathable fabric membranes are sold by W. L. Gore and Associates underthe trade name GORE-TEX®. The GORE-TEX®. The membranes repel liquidwater and can repel saliva, yet allow passage of water vapor and othergases. Pumping of the pharmaceutical composition into a zone enclosed inpart or entirely by the saliva-repelling membrane can increase thefraction of the drug that is buccally or sublingually absorbed, reducingthe flux of the composition or its drug from the proximity of the mucousmembrane into a part the oral cavity where it is diluted by saliva, thenswallowed. The saliva-repelling membrane can have a rim adhering to thebuccal or sublingual tissue. For adhesion to the buccal or sublingualtissue, the rim can have a mucoadhesive polymer coating described, forexample, in U.S. Pat. No. 4,900,552, 5,723,143, 5,744,155, 5,900,247,5,989,535, 5,989,535, 7,914,645, 8,735,374, 9,017,771, 9,044,475,9,044,500 or 9,161,890, each of which is incorporated herein byreference.

For buccal or sublingual delivery an optionally flow-controllingmetallic pipe or polymeric tubing can be connected at one end to thereservoir and at the other end to a mucosa-contacting, e.g. buccal orsublingual mucosa-contacting, manifold having one or more openingsthrough which the composition flows as a liquid or is extruded as apaste or gel. The pipe or tubing can be, for example 1-15 cm long, suchas 5-10 cm long. Its inner diameter can be between about 5 μm and about1 mm, such as between about 10 μm mm and about 0.5 mm. When metallic,the pipe can include, for example, titanium or one of its alloys, suchas annealed titanium of greater than about 98 weight % purity; or astainless steel; when polymeric, it could include, for examplepolyethylene terephthalate, a polyamide or a fluorinated polymer.

This invention includes the following itemized aspects and embodiments.

1. A pharmaceutical composition comprising a suspension that is a drugparticle-containing emulsion comprising (i) from 35% to 70% (w/w) drugparticles comprising levodopa and/or carbidopa, or salts thereof, (ii)from 19% to 30% (w/w) of one or more water-immiscible compounds, (iii)from 2% to 16% (w/w) water, and (iv) from 1% to 8% (w/w) surfactant,wherein the pharmaceutical composition is physically stable and suitablefor continuous or frequent intermittent intra-oral delivery.

2. A pharmaceutical composition comprising a suspension comprising (i)from about 35% to 70% (w/w) drug particles, (ii) from 19% to 30% (w/w)of one or more water-immiscible compounds, (iii) from 2% to 16% (w/w)water, and (iv) from 1% to 8% (w/w) surfactant, wherein thepharmaceutical composition is physically stable and suitable forcontinuous or frequent intermittent intra-oral delivery.

3. A pharmaceutical composition comprising a suspension comprising (i)an excess of one or more water-immiscible compounds over water, and (ii)from about 35% to 70% (w/w) drug particles, wherein the pharmaceuticalcomposition is physically stable for 6 months or more at 5° C.

4. The pharmaceutical composition of item 2 or 3, wherein saidpharmaceutical composition comprises an emulsion.

5. The pharmaceutical composition of any one of items 1 to 4, whereinsaid suspension is an extrudable, non-pourable emulsion.

6. The pharmaceutical composition of any one of items 1 to 5, whereinsaid suspension is physically stable for 12 months at 5° C.

7. The pharmaceutical composition of any one of items 1 to 5, whereinsaid suspension is physically stable for 12 months at 25° C.

8. The pharmaceutical composition of items 6 and 7, wherein after said12 months said suspension is physically stable for 48 hours at 37° C.

9. The pharmaceutical composition of any one of items 1 to 8, whereinsaid suspension comprises a continuous hydrophilic phase.

10. The pharmaceutical composition of any one of items 1 to 9, whereinthe concentration of drug in the pharmaceutical composition is at least1.75 M.

11. The pharmaceutical composition of any one of items 1 to 9,comprising from about 50% to about 70% (w/w) drug particles, wherein theconcentration of drug in the pharmaceutical composition is at least 3.0M.

12. The pharmaceutical composition of any one of items 1 to 11, whereinsaid one or more water-immiscible compounds melts or softens below 45°C.

13. The pharmaceutical composition of item 12, wherein said one or morewater-immiscible compounds melts or softens below 37° C.

14. The pharmaceutical composition of any one of items 1 to 13, whereinthe weight ratio of said one or more water-immiscible compounds to wateris greater than 1.0.

15. The pharmaceutical composition of item 14, wherein the weight ratioof said one or more water-immiscible compounds to water is greater than1.5.

16. The pharmaceutical composition of item 15, wherein the weight ratioof said one or more water-immiscible compounds to water is greater than2.0.

17. The pharmaceutical composition of item 16, wherein the weight ratioof said one or more water-immiscible compounds to water is greater than3.0.

18. The pharmaceutical composition of any one of items 1 to 17, whereinsaid one or more water-immiscible compounds comprises an oil.

19. The pharmaceutical composition of any one of items 1 to 18, whereinthe suspension comprises a continuous hydrophilic phase comprisinggreater than 50% (w/w) drug particles.

20. The pharmaceutical composition of any one of items 1 to 19, whereinsaid suspension comprises an oil in water emulsion.

21. The pharmaceutical composition of any one of items 1 to 20, whereinsaid suspension is free of polymers of a molecular mass greater than1,000 Daltons.

22. The pharmaceutical composition of any one of items 1 to 21, whereinsaid suspension has a dynamic viscosity of at least 100 cP at 37° C.

23. The pharmaceutical composition of item 22, wherein said suspensionhas a dynamic viscosity of at least 1,000 cP at 37° C.

24. The pharmaceutical composition of item 23, wherein said suspensionhas a dynamic viscosity of at least 10,000 cP at 37° C.

25. The pharmaceutical composition of item 24, wherein said suspensionhas a dynamic viscosity of at least 100,000 cP at 37° C.

26. The pharmaceutical composition of any one of items 1 to 25, whereinthe suspension comprises greater than 50% (w/w) drug particles.

27. The pharmaceutical composition of item 26, wherein the suspensioncomprises greater than 60% (w/w) drug particles.

28. The pharmaceutical composition of any one of items 1 to 27, whereinthe D₅₀ of the drug particles is less than or equal to 500 μm.

29. The pharmaceutical composition of any one of items 1 to 27, whereinthe D₅₀ of the drug particles is less than or equal to 250 μm.

30. The pharmaceutical composition of any one of items 1 to 27, whereinthe D₅₀ of the drug particles is less than or equal to 200 μm.

31. The pharmaceutical composition of any one of items 1 to 27, whereinthe D₅₀ of the drug particles is less than or equal to 150 μm.

32. The pharmaceutical composition of any one of items 1 to 27, whereinthe D₅₀ of the drug particles is less than or equal to 125 μm.

33. The pharmaceutical composition of any one of items 1 to 27, whereinthe D₅₀ of the drug particles is less than or equal to 100 μm.

34. The pharmaceutical composition of any one of items 1 to 27, whereinthe D₅₀ of the drug particles is less than or equal to 50 μm.

35. The pharmaceutical composition of any one of items 1 to 27, whereinthe D₅₀ of the drug particles is less than or equal to 25 μm.

36. The pharmaceutical composition of any one of items 1 to 35, whereinthe D₅₀ of the drug particles is greater than or equal to 1 μm.

37. The pharmaceutical composition of any one of items 1 to 35, whereinthe D₅₀ of the drug particles is greater than or equal to 3 μm.

38. The pharmaceutical composition of any one of items 1 to 35, whereinthe D₅₀ of the drug particles is greater than or equal to 5 μm.

39. The pharmaceutical composition of any one of items 1 to 35, whereinthe D₅₀ of the drug particles is greater than or equal to 10 μm.

40. The pharmaceutical composition of any one of items 1 to 34, whereinthe D₅₀ of the drug particles is greater than or equal to 25 μm.

41. The pharmaceutical composition of any one of items 1 to 27, whereinthe D₅₀ of the drug particles is 25±24 μm.

42. The pharmaceutical composition of any one of items 1 to 27, whereinthe D₅₀ of the drug particles is 75±25 μm.

43. The pharmaceutical composition of any one of items 1 to 27, whereinthe D₅₀ of the drug particles is 125±25 μm.

44. The pharmaceutical composition of any one of items 1 to 27, whereinthe D₅₀ of the drug particles is 175±25 μm.

45. The pharmaceutical composition of any one of items 1 to 44, whereinsaid suspension comprises less than or equal to about 16% (w/w) water.

46. The pharmaceutical composition of item 45, wherein said suspensioncomprises less than or equal to about 12% (w/w) water.

47. The pharmaceutical composition of item 46, wherein said suspensioncomprises less than or equal to about 9% (w/w) water.

48. The pharmaceutical composition of any one of items 3 to 47, whereinsaid suspension comprises greater than or equal to about 1% (w/w) water.

49. The pharmaceutical composition of any one of items 1 to 47, whereinsaid suspension comprises greater than or equal to about 2% (w/w) water.

50. The pharmaceutical composition of any one of items 1 to 47, whereinsaid suspension comprises greater than or equal to about 3% (w/w) water.

51. The pharmaceutical composition of any one of items 1 to 44, whereinsaid suspension comprises 4±2% (w/w) water.

52. The pharmaceutical composition of any one of items 1 to 44, whereinsaid suspension comprises 8±2% (w/w) water.

53. The pharmaceutical composition of any one of items 1 to 44, whereinsaid suspension comprises 13±3% (w/w) water.

54. The pharmaceutical composition of any one of items 1 to 53, whereinsaid one or more water-immiscible compounds comprises an oil selectedfrom a saturated fatty acid triglyceride, an unsaturated fatty acidtriglyceride, a mixed saturated and unsaturated fatty acid triglyceride,a medium-chain fatty acid triglyceride, canola oil, coconut oil, palmoil, olive oil, soybean oil, sesame oil, corn oil, or mineral oil.

55. The pharmaceutical composition of item 54, wherein said oil is asaturated fatty acid triglyceride.

56. The pharmaceutical composition of item 54, wherein said oil is amedium-chain fatty acid triglyceride oil.

57. The pharmaceutical composition of item 54, wherein said oil is acanola oil.

58. The pharmaceutical composition of item 54, wherein said oil iscoconut oil.

59. The pharmaceutical composition of item 56, wherein said oil is aMiglyol® or chemical equivalent.

60. The pharmaceutical composition of item 54, wherein said oil is atriglyceride of one or more C₆-C₂₄ fatty acids.

61. The pharmaceutical composition of item 60, wherein said oil is atriglyceride of one or more C₈-C₁₆ fatty acids.

62. The pharmaceutical composition of item 54, wherein at least 50%(w/w) of said one or more water-immiscible compounds is a triglycerideof one or more C₈-C₁₂ fatty acids.

63. The pharmaceutical composition of item 60, wherein said oil is atriglyceride of C₈-C₁₂ fatty acids, C₁₄-C₁₈ fatty acids, or C₂₀-C₂₄fatty acids, or a mixture thereof.

64. The pharmaceutical composition of any one of items 54 to 63, whereinsaid suspension comprises less than or equal to about 30% (w/w) of saidoil.

65. The pharmaceutical composition of any one of items 54 to 63, whereinsaid suspension comprises less than or equal to about 29% (w/w) of saidoil.

66. The pharmaceutical composition of any one of items 54 to 63, whereinsaid suspension comprises less than or equal to about 27% (w/w) of saidoil.

67. The pharmaceutical composition of any one of items 54 to 63, whereinsaid suspension comprises less than or equal to about 25% (w/w) of saidoil.

68. The pharmaceutical composition of any one of items 54 to 67, whereinsaid suspension comprises greater than or equal to about 19% (w/w) ofsaid oil.

69. The pharmaceutical composition of any one of items 54 to 67, whereinsaid suspension comprises greater than or equal to about 21% (w/w) ofsaid oil.

70. The pharmaceutical composition of any one of items 54 to 67, whereinsaid suspension comprises greater than or equal to about 23% (w/w) ofsaid oil.

71. The pharmaceutical composition of any one of items 54 to 63, whereinsaid suspension comprises 20±2% (w/w) of said oil.

72. The pharmaceutical composition of any one of items 54 to 63, whereinsaid suspension comprises 24±2% (w/w) of said oil.

73. The pharmaceutical composition of any one of items 54 to 63, whereinsaid suspension comprises 28±2% (w/w) of said oil.

74. The pharmaceutical composition of any one of items 1 to 73, whereinsaid pharmaceutical composition comprises a non-ionic surfactant.

75. The pharmaceutical composition of item 74, wherein said non-ionicsurfactant comprises a polyglycolized glyceride, a poloxamer, an alkylsaccharide, an ester saccharide, or a polysorbate surfactant.

76. The pharmaceutical composition of item 75, wherein said non-ionicsurfactant comprises a poloxamer or wherein the poloxamer is poloxamer188.

77. The pharmaceutical composition of item 75, wherein said non-ionicsurfactant comprises a polyglycolized glyceride that is apolyethoxylated castor oil.

78. The pharmaceutical composition of item 75, wherein said non-ionicsurfactant comprises a polysorbate surfactant that is Polysorbate 60.

79. The pharmaceutical composition of any one of items 1 to 78, whereinsaid suspension comprises less than or equal to about 8% (w/w) of saidsurfactant.

80. The pharmaceutical composition of any one of items 1 to 78, whereinsaid suspension comprises less than or equal to about 7% (w/w) of saidsurfactant.

81. The pharmaceutical composition of any one of items 1 to 78, whereinsaid suspension comprises less than or equal to about 6% (w/w) of saidsurfactant.

82. The pharmaceutical composition of any one of items 1 to 81, whereinsaid suspension comprises greater than or equal to about 2% (w/w) ofsaid surfactant.

83. The pharmaceutical composition of any one of items 1 to 81, whereinsaid suspension comprises greater than or equal to about 3% (w/w) ofsaid surfactant.

84. The pharmaceutical composition of any one of items 1 to 81, whereinsaid suspension comprises greater than or equal to about 4% (w/w) ofsaid surfactant.

85. The pharmaceutical composition of any one of items 1 to 78, whereinsaid suspension comprises about 5±2% (w/w) of said surfactant.

86. The pharmaceutical composition of any one of items 1 to 85, furthercomprising an antioxidant or a taste modifying agent.

87. The pharmaceutical composition of item 86, wherein said antioxidantis oil soluble.

88. The pharmaceutical composition of item 86, wherein said antioxidantis Vitamin E, TPGS, ascorbylpalmitate, a tocopherol, thioglycerol,thioglycolic acid, vitamin A, propyl gallate, octyl gallate,butylhydroxyanisole, or butylhydroxytoluene.

89. The pharmaceutical composition of any one of items 1 to 88, whereinpH of said suspension is less than or equal to about 7.

90. The pharmaceutical composition of item 89, wherein the pH of saidpharmaceutical composition is less than or equal to about 5.0.

91. The pharmaceutical composition of item 88, wherein the pH of saidpharmaceutical composition is less than or equal to about 4.0.

92. The pharmaceutical composition of any one of items 87 to 89, whereinthe pH of said pharmaceutical composition is greater than or equal toabout 3.

93. The pharmaceutical composition of item 90, wherein the pH of thecomposition measured by inserting a glass walled pH electrode into theformulation is less than pH 5 and remains less than pH 5 after 3 monthsstorage at 25° C.

94. The pharmaceutical composition of item 91, wherein the pH is andremains less than pH 4 after 3 months storage at 25° C.

95. The pharmaceutical composition of item 94, wherein the pH equals oris less than pH 3 after 3 months storage at 25° C.

96. The pharmaceutical composition of any one of items 1 to 95,comprising a bacteriostatic or a fungistatic agent.

97. The pharmaceutical composition of item 96, wherein the agentcomprises benzoic acid or a benzoate salt.

98. The pharmaceutical composition of item 97, wherein the combinedconcentrations of benzoic acid and benzoate salt are between 0.1 percentby weight and 1 percent by weight.

99. The pharmaceutical composition of any one of items 1 to 98, furthercomprising a transition metal ion complexing agent or a salt thereof.

100. The pharmaceutical composition of item 99, wherein the transitionmetal ion complexing agent is EDTA or a salt thereof.

101. The pharmaceutical composition of item 100, wherein the combinedconcentrations of EDTA and its salt or salts is between 0.05 weight %and 0.25 weight %.

102. The pharmaceutical composition of any one of items 1 to 101,further comprising a sulfur comprising compound.

103. The pharmaceutical composition of item 102, wherein the sulfurcomprising compound reacts at 25±3° C. with dopaquinone or with quinoneformed by oxidation of carbidopa.

104. The pharmaceutical composition of item 103, wherein the sulfurcomprising compound is cysteine and N-acetylcysteine.

105. The pharmaceutical composition of any one of items 1 to 104,wherein the shelf life of said pharmaceutical composition is 1 year orlonger at 5±3° C.

106. The pharmaceutical composition of any one of items 1 to 104,wherein the shelf life of said pharmaceutical composition is 1 year orlonger at 25±3° C.

107. The pharmaceutical composition of any one of items 2 to 106,wherein said drug particles comprise levodopa or a levodopa prodrug, orcarbidopa or a carbidopa prodrug, benserazide, or any mixture thereof.

108. The pharmaceutical composition of item 107, wherein said drugparticles comprise levodopa and/or carbidopa.

109. The pharmaceutical composition of item 107 or 108, comprisingcarbidopa and less than 2 μg of hydrazine per mg of drug after 1 weekstorage under ambient air at 60° C.

110. The pharmaceutical composition of item 107 or 108, comprisingcarbidopa and less than 1 μg of hydrazine per mg of drug after 1 weekstorage under ambient air at 60° C.

111. The pharmaceutical composition of item 107 or 108, wherein saiddrug particles comprise carbidopa, and further comprising less than 8 μgof hydrazine per mg of carbidopa after 6 or 12 month storage at 5±3° C.

112. The pharmaceutical composition of item 107 or 108, wherein saiddrug particles comprise carbidopa, and further comprising less than 8 μgof hydrazine per mg of carbidopa after 6 or 12 month storage at 25±3° C.

113. The pharmaceutical composition of item 111 or 112, wherein saidcomposition comprises less than 4 μg of hydrazine per mg of carbidopaafter said 12 month storage.

114. The pharmaceutical composition of item 113, wherein saidcomposition comprises less than 1 μg of hydrazine per mg of carbidopaafter said 12 month storage.

115. The pharmaceutical composition of any one of items 2 to 106,wherein said drug particles comprise one or more allergens, allergenextracts, or allergen derivatives.

116. The pharmaceutical composition of item 115, wherein said one ormore allergens is pollen, a part of a mite, or a component of the felineor canine skin, or an extract or a conversion product thereof.

117. The pharmaceutical composition of any one of items 1 to 116,wherein said suspension does not cream or sediment when centrifuged for1 hour at an acceleration of about 5,000 G at 25±3° C.

118. The pharmaceutical composition of item 117, wherein said suspensiondoes not cream or sediment when centrifuged for 1 hour at anacceleration of about 10,000 G at 25±3° C.

119. The pharmaceutical composition of item 118, wherein said suspensiondoes not cream or sediment when centrifuged for 1 hour at anacceleration of about 16,000 G at 25±3° C.

120. The pharmaceutical composition of any one of items 1 to 116,wherein said pharmaceutical composition does not cream or sediment whenstored for 12 months at 5±3° C.

121. The pharmaceutical composition of any one of items 1 to 116,wherein said pharmaceutical composition does not cream or sediment whenstored for 12 months at 25±3° C.

122. The pharmaceutical composition of any one of items 117 to 121,wherein after said centrifugation or said storage the concentrations ofdrug in the layer containing the top 20 volume % and the layercontaining the bottom 20 volume % of the composition differ by less than10%.

123. The pharmaceutical composition of item 122, wherein after saidcentrifugation or said storage the concentrations of drug in the layercontaining the top 20 volume % and the layer containing the bottom 20volume % of the composition differ by less than 6%.

124. The pharmaceutical composition of item 123, wherein after saidcentrifugation or said storage the concentrations of drug in the layercontaining the top 20 volume % and the layer containing the bottom 20volume % of the composition differ by less than 4%.

125. The pharmaceutical composition of item 124, wherein after saidcentrifugation or said storage the concentrations of drug in the layercontaining the top 20 volume % and the layer containing the bottom 20volume % of the composition differ by less than 2%.

126. The pharmaceutical composition of any one of items 117 to 121,wherein after said centrifugation or said storage there is no visiblecreaming or sedimentation.

127. The pharmaceutical composition of any one of items 1 to 126,wherein said pharmaceutical composition has substantially no taste.

128. A pharmaceutical composition comprising a suspension comprising (i)from about 20% to about 80% (w/w) solid excipients; (ii) from about 5%to 60% (w/w) drug particles, (iii) from 19% to 30% (w/w) of one or morewater-immiscible compounds, (iv) from 2% to 25% (w/w) water, and (v)from 1% to 10% (w/w) surfactant, wherein the pharmaceutical compositionis physically stable and suitable for continuous or frequentintermittent intra-oral delivery.

129. The pharmaceutical composition of item 128, wherein saidpharmaceutical composition comprises a paste.

130. The pharmaceutical composition of item 128 or 129, wherein saidpharmaceutical composition comprises an emulsion.

131. The pharmaceutical composition of any of items 128 to 130, whereinsaid suspension is physically stable for 12 months at 5° C.

132. The pharmaceutical composition of any of items 128 to 131, whereinsaid suspension is physically stable for 12 months at 25° C.

133. The pharmaceutical composition of item 131 or 132, wherein aftersaid 12 months said suspension is physically stable for 48 hours at 37°C.

134. The pharmaceutical composition of item 128 or 133, wherein theconcentration of drug in the pharmaceutical composition is between about50 mg/mL and about 500 mg/mL

135. The pharmaceutical composition of any of one of items 128 to 134,wherein the concentration of solid excipient in the pharmaceuticalcomposition is between 200 mg/mL and about 800 mg/mL.

136. The pharmaceutical composition of any of one of items 128 to 135,wherein said solid excipient comprises cellulose, a cellulosederivative, an amino acid, titanium dioxide, calcium silicate, orcalcium phosphate.

137. The pharmaceutical composition of any one of items 128 to 136,wherein said drug comprises Tizanidine, Midodrine, Metoclopramide,Captopril, Treprostinil, Bitolterol, Oxybutinin, Darifenacin, or apharmaceutically acceptable salt thereof.

138. The pharmaceutical composition of any one of items 128 to 136,wherein said drug comprises baclofen and said pharmaceutical compositioncomprises baclofen.

139. The pharmaceutical composition of any one of items 128 to 137having a viscosity greater than 10,000 cP at 37° C.

140. A pharmaceutical composition suitable for continuous infusion inthe mouth comprising: a solution, an oil-in-water emulsion, awater-in-oil emulsion, or a solid particle comprising a suspension ofbetween 20 mg/mL and 150 mg/mL of a drug selected from Baclofen,Tizanidine, Midodrine, Metoclopramide, Captopril, Treprostinil,Bitolterol, Oxybutinin, Darifenacin.

141. The pharmaceutical composition of item 140, further comprising athickener.

142. The pharmaceutical composition of item 140 or 141 wherein theviscosity of said pharmaceutical composition is greater than 100 cP,1,000 cP, 10,000, or 100,000 cP at about 37° C.

143. The pharmaceutical composition of any one of items 140 to 142,further comprising a surfactant.

144. An extrudable pharmaceutical composition suitable for continuousinfusion in the mouth having a pH of from 3 to 10 comprising a magnesiumcompound, a zinc compound, or an iron compound at a concentrationbetween 60 mg/mL to 1,600 mg/mL.

145. The pharmaceutical composition of item 144, further comprising agelling agent or a thickener.

146. The pharmaceutical composition of item 144 or 145, wherein theviscosity of said pharmaceutical composition is greater than 100 cP,1,000 cP, 10,000 cP, or 100,000 cP at about 37° C.

147. The pharmaceutical composition of item 146, wherein thepharmaceutical composition comprises a magnesium compound and the Mg²⁺concentration in the pharmaceutical composition is greater than 200mg/mL.

148. A pharmaceutical composition suitable for continuous infusion inthe mouth comprising a solution, suspension or gel comprising between0.1 mg/mL and 20 mg/mL of a drug selected from Tizanidine, Iloprost,Beraprost, Ciclesonide, Flunisolide, Budesonide, Beclomethasone,Mometasone, Vilanterol, Levosalbutamol sulfate, Salbutamol, Salmeterol,Glycopyrronium bromide, Ipatropium bromide, Aclidinium bromide,Hexoprenaline sulfate, Pirbuterol, Fenoterol, Terbutaline,Metaproterenol, Tolterodine tartarate.

149. The pharmaceutical composition of item 148, further comprising athickener.

150. The pharmaceutical composition of item 148 or 149 wherein theviscosity of said pharmaceutical composition is greater than 100 cP,1,000 cP, 10,000 cP, or 100,000 cP at about 37° C.

151. The pharmaceutical composition of any one of items 148 to 150,further comprising a surfactant.

152. A drug delivery device configured to be removably inserted in apatient's mouth and for continuous or semi-continuous intraoraladministration a drug, said device comprising a propellant-driven pumpcomprising a rigid housing, said rigid housing comprising a wall of afirst chamber containing a drug-comprising fluid and a wall of a secondchamber containing a propellant.

153. The drug delivery device of item 152, comprising a flexible and/ordeformable propellant-impermeable diaphragm separating said firstchamber from said second chamber.

154. The drug delivery device of item 153, wherein the density of thepropellant-impermeable diaphragm is greater than 2.0 g per cm³ at 25° C.

155. The drug delivery device of item 153 or 154, wherein said diaphragmcomprises a wall of said first chamber and a wall of said secondchamber.

156. The drug delivery device of any one of items 153 to 155, whereinsaid diaphragm is metallic.

157. The drug delivery device of item 156, wherein the metallicdiaphragm comprises tin or silver or aluminum or copper or an alloy oftin or of silver or of aluminum or of copper.

158. The drug delivery device of item 157, wherein the metallicdiaphragm comprises silver or an alloy of silver.

159. The drug delivery device of item 157, wherein the metallicdiaphragm comprises tin or an alloy of tin.

160. The drug delivery device of any one of items 153 to 159, whereinsaid diaphragm is shaped to substantially conform to the interiorhousing wall of said first chamber.

161. The drug delivery device of any one of items 153 to 159, whereinsaid diaphragm is shaped to substantially conform to the interiorhousing wall of said second chamber.

162. The drug delivery device of any one of items 153 to 161, whereinthe thickness of said diaphragm is between 10 μm and 250 μm, between 20μm and 125 μm, or between 25 μm and 75 μm.

163. The drug delivery device of any one of items 153 to 162, whereinthe thickness of said diaphragm varies across the interior of thehousing by less than ±25%.

164. The drug delivery device of any one of items 153 to 162, whereinthe thickness of said diaphragm varies across the interior of thehousing by less than ±10%.

165. The drug delivery device of any one of items 153 to 162, whereinsaid diaphragm comprises a rim that is thicker than the center of saiddiaphragm.

166. The drug delivery device of item 165, wherein the thickness of therim is at least 1.5 times greater than the thickness of the center ofsaid diaphragm.

167. The drug delivery device of item 166, where the thickness of therim is between 1.5 times and 2 times the thickness of the center of saiddiaphragm.

168. The drug delivery device of item 167, where the thickness of therim is between 2 times and 3 times the thickness of the center of saiddiaphragm.

169. The drug delivery device of item 168, where the thickness of therim is 3 times or more the thickness of the center of said diaphragm.

170. The drug delivery device of any one of items 153 to 169, whereinsaid diaphragm is folded, pleated, or scored.

171. A method of forming said diaphragm of any one of items 153 to 170,by stamping, hot-stamping, electroplating, electroless plating, orhydroforming.

172. The drug delivery device of any of items 152 to 171, wherein thedevice is hermetically sealed except for one or more orifices for drugfilling or drug delivery.

173. The drug delivery device of item 172, wherein the one or moreorifices for drug filling or drug delivery are hermetically ornon-hermetically sealed.

174. The drug delivery device of item 173, wherein the one or moreorifices for drug filling or delivery are hermetically sealed.

175. The drug delivery device of any one of items 152 to 174, whereinthe propellant chamber is hermetically sealed and comprises ahermetically sealed orifice for filling with propellant.

176. The drug delivery device of any one of items 172 to 175, whereinthe drug chamber comprises two, three, or more hermetically sealable orsealed orifices for filling with drug or for drug delivery.

177. The drug delivery device of any one of items 153 to 176, whereinsaid rigid housing and said diaphragm are joined by a hermeticallysealing weld.

178. The drug delivery device of item 177, where the hermeticallysealing weld prevents the influx of air and water vapor or the outfluxof water vapor, drug or propellant.

179. The drug delivery device of item 178, where the hermeticallysealing weld prevents the influx of air or oxygen.

180. The drug delivery device of any one of items 177 to 179, whereinthe hermetically sealing weld prevents the influx or the outflux ofhelium.

181. A method of forming the weld of any one of items 177 to 180,comprising welding said rigid housing and said diaphragm to form ahermetic seal.

182. The method of item 181, wherein the method comprises resistancewelding, laser welding or electron beam welding.

183. The method of item 182, wherein the method comprises resistancewelding.

184. The method of item 183, wherein the method also comprisespreheating the housing and said diaphragm.

185. The method of any one of items 181 to 184, wherein the method alsocomprises annealing at a temperature between 400° C. and 700° C. for 15minutes or more.

186. The drug delivery device of any one of items 152 to 185, whereinsaid rigid housing comprises a metal, a ceramic, or a composite of apolymer reinforced by fibers.

187. The drug delivery device of item 186, wherein the fibersreinforcing the polymer comprise carbon fibers, glass fibers, or metalfibers.

188. The drug delivery device of any one of items 152 to 187, whereinsaid rigid housing comprises a material having at 25±3° C. a yieldstrength greater than 100 MPa.

189. The drug delivery device of any one of items 152 to 187, whereinsaid rigid housing comprises a material having at 25±3° C. a tensileyield strength greater than 100 MPa.

190. The drug delivery device of any one of items 152 to 187, whereinsaid rigid housing comprises a material having at 25±3° C. a modulus ofelasticity greater than 30 GPa.

191. The drug delivery device of any one of items 152 to 187, whereinsaid rigid housing comprises a material having at 25±3° C. a Brinellhardness greater than 200 MPa.

192. The drug delivery device of any one of items 152 to 191, whereinsaid rigid housing comprises a material having a density greater than2.5 g/cm³ at 25±3° C.

193. The drug delivery device of any one of items 152 to 192, whereinsaid rigid housing comprises a metal having a density greater than 2.5g/cm³.

194. The drug delivery device of item 193, wherein said rigid housingcomprises a metal having a density greater than 3.5 g/cm³.

195. The drug delivery device of item 194, wherein said rigid housingcomprises a metal having a density equal to or greater than 4.5 g/cm³.

196. The drug delivery device of any one of items 193 to 195, whereinsaid rigid housing comprises a metal selected from the group titanium oriron or aluminum or molybdenum or tungsten or an alloy of titanium oriron or aluminum or molybdenum or tungsten.

197. The drug delivery device of item 196, wherein said rigid housingcomprises titanium or an alloy of titanium.

198. The drug delivery device of item 197, wherein a metallic diaphragmis welded to said rigid housing comprising titanium or an alloy oftitanium.

199. The drug delivery device of item 197 or 198, wherein said diaphragmcomprises silver or an alloy of silver.

200. The drug delivery device of item 196, wherein the metal comprisesiron or an alloy of iron.

201. The drug delivery device of item 200, wherein said diaphragmcomprises iron or an alloy of iron.

202. The drug delivery device of item 200, wherein the metallicdiaphragm comprises silver or an alloy of silver.

203. The drug delivery device of any one of items 193 to 202, whereinneither the metal of said rigid housing nor of the metal of saidmetallic diaphragm corrodes visibly after 3 months when the housingmetal and said diaphragm metal are electrically contacted and areimmersed in an air exposed 0.1 M citrate buffer solution of pH 4.0 at23±3° C.

204. The drug delivery device of any one of items 193 to 202, whereinneither the metal of said rigid housing nor the metal of said metallicdiaphragm corrodes visibly after 3 months when the housing metal andsaid diaphragm metal are electrically contacted and are immersed in asubstantially de-oxygenated 0.1 M citrate buffer solution of pH 4.0 at23±3° C.

205. The drug delivery device of item 204, wherein the density of thecurrent flowing between two electrically shorted electrodes of aboutequal area, one of the metal of said rigid housing and the other of themetal of said diaphragm, is less than 2 μA cm⁻² after the electrodes areimmersed in a substantially de-oxygenated 0.1 M citrate buffer solutionof pH 4.0 at 23±3° C. for 24 hours.

206. The drug delivery device of item 205, wherein said current densityis less than 0.5 μA cm⁻².

207. The drug delivery device of item 206, wherein said current densityis less than 0.1 μA cm⁻².

208. The drug delivery device of any of items 152 to 207, wherein theshapes of the interior housing wall of said first chamber and theinterior housing wall of said second chamber are substantially mirrorimages of each other excepting for grooves or ports for flow ofdrug-comprising fluid to the drug exit orifice.

209. The drug delivery device of any one of items 152 to 208, whereinsaid first chamber comprises one or more interior channels, grooves, ortubes for flow of drug-comprising fluid to the drug exit orifice.

210. The drug delivery device of item 209, wherein at least one channel,groove, or tube is not blocked by the diaphragm after more than 60weight % of the drug is depleted.

211. The drug delivery device of item 210, wherein at least one channel,groove, or tube is not blocked by the diaphragm after more than 75weight % of the drug is depleted.

212. The drug delivery device of item 211, wherein at least one channel,groove, or tube is not blocked by the diaphragm after more than 85weight % of the drug is depleted.

213. The drug delivery device of item 212, wherein at least one channel,groove, or tube is not blocked by the diaphragm after more than 95weight % of the drug is depleted.

214. The drug delivery device of item 209, wherein at least one channel,groove, or tube is not blocked by the diaphragm when said diaphragm hasbeen fully extended into the drug chamber and drug flow hassubstantially stopped.

215. The drug delivery device of item 209, wherein a housing wallcomprises the at least one channel, groove, or tube.

216. The drug delivery device of any one of items 209 to 215, wherein aninsert comprises the at least one channel, groove, or tube.

217. The drug delivery device of any one of items 209 to 216, whereinsaid at least one channel, groove, or tube comprises one or more flowrestrictors that substantially control the rate of drug delivery.

218. The drug delivery device of any one of items 153 to 217, whereinsaid diaphragm is shaped and sized so that it contacts 0%-10%, 11%-20%,21%-30%, 31%-40%, or 41%-50% of the interior surface area of the drugchamber (excluding the surface area of the diaphragm itself) afterdelivery of 85%, 90%, or 95% of the starting drug product in the drugchamber.

219. The drug delivery device of any one of items 153 to 218, whereinsaid diaphragm is shaped and sized so that it does not substantiallyblock the flow of said pharmaceutical composition from the exit orificeafter 85%, 90%, or 95% of the starting drug product in the drug chamberhas been delivered.

220. A drug delivery device configured to be removably inserted in apatient's mouth and for continuous or semi-continuous intraoraladministration of a drug, said device comprising:

-   -   (i) a first chamber containing a drug-comprising fluid;    -   (ii) a second chamber containing a propellant; and    -   (iii) a flexible and/or deformable diaphragm separating said        first chamber from said second chamber;    -   (iv) wherein 75%-85%, 86%-95%, or >95% of the drug-comprising        fluid is dispensed while the delivery rate varies by less than        ±20%, ±15%, ±10%, or ±5%, over a period of at least 4, 8, 16, or        24 hours.

221. The drug delivery device of any one of items 152 to 220, whereinsaid pump comprises a liquid propellant, said liquid propellant having aboiling point of less than 37° C. at sea level atmospheric pressure.

222. The drug delivery device of item 221, wherein said liquidpropellant is a hydrocarbon, a halocarbon, a hydrofluoralkane, an ester,or an ether.

223. The drug delivery device of item 221, wherein said liquidpropellant is isopentane, trifluorochloromethane, dichlorofluoromethane,1-fluorobutane, 2-fluorobutane, 1,2-difluoroethane, methyl ethyl ether,2-butene, butane, 1-fluoropropane, 1-butene, 2-fluoropropane,1,1-difluoroethane, cyclopropene, propane, propene, or diethyl ether.

224. The drug delivery device of item 221, wherein said liquidpropellant is 1,1,1,2-tetrafluoroethane,1,1,1,2,3,3,3-heptafluoropropane, 1,1,1,3,3,3-hexafluoropropane,octafluorocyclobutane or isopentane.

225. The drug delivery device of item 221, wherein said propellant isisopentane, trifluorochloromethane, dichlorofluoromethane, or1,1,1,2-tetrafluoroethane.

226. The drug delivery device of any one of items 221 to 225, whereinsaid propellant has a vapor pressure of greater than 1.5 bar and lessthan 10 bar, or greater than 1.5 bar and less than 20 bar, at 37° C.

227. The drug delivery device of item 226, wherein said propellant has avapor pressure of greater than 2.0 bar and less than 7 bar, or greaterthan 2.0 bar and less than 15 bar at 37° C.

228. The drug delivery device of item 227, wherein said propellant has avapor pressure of greater than 3.0 bar and less than 6 bar, or greaterthan 3.0 bar and less than 10 bar, at 37° C.

229. The drug delivery device of any one of items 221 to 228, wherein(i) said propellant has a vapor pressure of greater than 2.1 bar at 37°C., and (ii) the average rate of drug delivery increases or decreases byless than ±20% across the atmospheric pressure range between 0.782 barand 1.013 bar.

230. The drug delivery device of item 229, wherein (i) said propellanthas a vapor pressure of greater than 3.2 bar at 37° C., and (ii) theaverage rate of drug delivery increases or decreases by less than ±10%across the atmospheric pressure range between 0.782 bar and 1.013 bar.

231. The drug delivery device of item 230, wherein (i) said propellanthas a vapor pressure of greater than 4.7 bar at 37° C., and (ii) theaverage rate of drug delivery increases or decreases by less than ±6%across the atmospheric pressure range between 0.782 bar and 1.013 bar.

232. The drug delivery device of any one of items 152 to 231, comprisinga pharmaceutical composition of any of items 1-151.

233. A drug delivery device configured to be removably inserted in apatient's mouth and for continuous or semi-continuous intraoraladministration of a drug, said device comprising:

-   -   (i) a fastener to removably secure said drug delivery device to        a surface of said patient's mouth;    -   (ii) an electrical or mechanical pump; and    -   (iii) an oral liquid impermeable drug reservoir containing any        of the pharmaceutical compositions of any one of items 1 to 151,        the volume of said drug reservoir being from 0.1 mL to 5 mL.

234. A drug delivery device configured to be removably inserted in apatient's mouth and for continuous or semi-continuous intraoraladministration a drug, said device comprising:

-   -   (i) a fastener to removably secure said drug delivery device to        a surface of said patient's mouth;    -   (ii) an electrical or mechanical pump;    -   (iii) an oral liquid impermeable drug reservoir containing any        of the pharmaceutical compositions of any one of items 1 to 151,        the volume of said drug reservoir being from 0.1 mL to 5 mL; and    -   (iv) an automatic stop/start.

235. The drug delivery device of item 234, wherein said drug deliverydevice is configured to be automatically stopped upon one or more of thefollowing: (a) the drug delivery device, the pump, and/or the oralliquid impermeable reservoir are removed from the mouth; (b) the drugdelivery device, the pump, and/or the oral liquid impermeable reservoirare disconnected from the fastener; or (c) the oral liquid impermeablereservoir is disconnected from the pump.

236. The drug delivery device of item 234 or 235, wherein said drugdelivery device is configured to be automatically started upon one ormore of the following: (a) the drug delivery device, the pump, and/orthe oral liquid impermeable reservoir are inserted into the mouth; (b)the drug delivery device, the pump, and/or the oral liquid impermeablereservoir are connected to the fastener; or (c) the oral liquidimpermeable reservoir is connected to the pump.

237. The drug delivery device of any one of items 234 to 236, whereinsaid automatic stop/start is selected from: a pressure sensitive switch,a clip, a fluidic channel that kinks, a clutch, a sensor, or a cap.

238. The drug delivery device of any one of items 234 to 237, furthercomprising a suction-induced flow limiter, a temperature-induced flowlimiter, bite-resistant structural supports, or a pressure-invariantmechanical pump.

239. A drug delivery device configured to be removably inserted in apatient's mouth and for continuous or semi-continuous intraoraladministration of a drug, said device comprising:

-   -   (i) a fastener to removably secure said drug delivery device to        a surface of said patient's mouth;    -   (ii) a mechanical pump;    -   (iii) an oral liquid impermeable drug reservoir containing any        of the pharmaceutical compositions of any one of items 1 to 151,        the volume of said drug reservoir being from 0.1 mL to 5 mL; and    -   (iv) a suction-induced flow limiter.

240. The drug delivery device of item 239, wherein said suction-inducedflow limiter comprises pressurized surfaces that are in fluidic (gasand/or liquid) contact with the ambient atmosphere via one or more portsor openings in the housing of the drug delivery device.

241. The drug delivery device of item 239, wherein said suction-inducedflow limiter is selected from the group consisting of a deformablechannel, a deflectable diaphragm, a compliant accumulator, an inlinevacuum-relief valve, and a float valve.

242. The drug delivery device of any one of items 239 to 241, whereinsaid suction-induced flow limiter is configured to prevent the deliveryof a bolus greater than about 5%, 3%, or 1% of the contents of a freshdrug reservoir, when the ambient pressure drops by 0.14 bar for a periodof one minute.

243. The device of any one of items 239 to 242, further comprising anautomatic stop/start, a temperature-induced flow limiter, bite-resistantstructural supports, or a pressure-invariant mechanical pump.

244. A drug delivery device configured to be removably inserted in apatient's mouth and for continuous or semi-continuous intraoraladministration of a drug, said device comprising:

-   -   (i) a fastener to removably secure said drug delivery device to        a surface of said patient's mouth;    -   (ii) an electrical or mechanical pump;    -   (iii) an oral liquid impermeable drug reservoir containing any        of the pharmaceutical compositions of any one of items 1 to 151,        the volume of said drug reservoir being from 0.1 mL to 5 mL; and    -   (iv) a temperature-induced flow limiter.

245. The drug delivery device of item 244, wherein saidtemperature-induced flow limiter comprises insulation with a material oflow thermal conductivity proximate the drug reservoir and/or the pump.

246. The drug delivery device of item 244 or 245, wherein saidtemperature-induced flow limiter comprises an elastomer whose force in afresh reservoir increases by less than 30% when the oral temperature israised from 37° C. to 55° C. for a period of one minute.

247. The drug delivery device of item 244 or 245, wherein said pumpcomprises a spring and said temperature-induced flow limiter comprises aspring configured to produce a force in a fresh reservoir that increasesby less than 30% when the oral temperature is raised from 37° C. to 55°C. for a period of one minute.

248. The drug delivery device of item 244, wherein saidtemperature-induced flow limiter comprises a spring comprising a 300series stainless steel, titanium, Inconel, and fully austenitic Nitinol.

249. The drug delivery device of item 244 or 245, wherein said pump isgas-driven and said temperature-induced flow limiter comprises a gashaving a volume of less than 40% of the volume of a filled drugreservoir in a fresh reservoir at 37° C. and 1.013 bar.

250. The drug delivery device of item 244 or 245, wherein said pump ispropellant-driven and said temperature-induced flow limiter comprises apropellant having a pressure that increases by less than about 80%, 60%,or 40% when the oral temperature is raised from 37° C. to 55° C. for aperiod of one minute.

251. The drug delivery device of any one of items 244 to 250, furthercomprising a suction-induced flow limiter, an automatic stop/start,bite-resistant structural supports, or a pressure-invariant mechanicalpump.

252. A drug delivery device configured to be removably inserted in apatient's mouth and for continuous or semi-continuous intraoraladministration of a drug, said device comprising:

-   -   (i) a fastener to removably secure said drug delivery device to        a surface of said patient's mouth;    -   (ii) an electrical or mechanical pump;    -   (iii) an oral liquid impermeable drug reservoir containing any        of the pharmaceutical compositions of any one of items 1 to 151,        the volume of said drug reservoir being from 0.1 mL to 5 mL; and    -   (iv) bite-resistant structural supports.

253. The drug delivery device of item 252, wherein said bite-resistantstructural supports are selected from: a housing that encapsulates theentire drug reservoir and pump components; posts; ribs; or a pottingmaterial.

254. The drug delivery device of item 252 or 253, further comprising asuction-induced flow limiter, an automatic stop/start, atemperature-induced flow limiter, or a pressure-invariant mechanicalpump.

255. A drug delivery device configured to be removably inserted in apatient's mouth and for continuous or semi-continuous intraoraladministration of a drug, said device comprising:

-   -   (i) a fastener to removably secure said drug delivery device to        a surface of said patient's mouth;    -   (ii) a pressure-invariant mechanical pump; and    -   (iii) an oral liquid impermeable drug reservoir containing any        of the pharmaceutical compositions of any one of items 1 to 151,        the volume of said drug reservoir being from 0.1 mL to 5 mL.

256. The drug delivery device of item 255, wherein saidpressure-invariant mechanical pump comprises pressurized surfaces thatare in fluidic (gas and/or liquid) contact with the ambient atmospherevia one or more ports or openings in the housing of the drug deliverydevice.

257. The drug delivery device of item 255 or 256, wherein saidpressure-invariant mechanical pump is configured to maintain an internalpressure of greater than or equal to about 2 bar.

258. The drug delivery device of item 257, wherein saidpressure-invariant mechanical pump is configured to maintain an internalpressure of greater than or equal to about 3 bar.

259. The drug delivery device of item 258, wherein saidpressure-invariant mechanical pump is configured to maintain an internalpressure of greater than or equal to about 4 bar.

260. The drug delivery device of any one of items 255 to 259, whereinsaid pressure-invariant mechanical pump is configured such that theaverage rate of drug delivery increases or decreases by less than about20%, about 10%, or about 5% at 1.013 bar and at 0.782 bar, as comparedto said average rate of delivery at 0.898 bar.

261. The drug delivery device of any one of items 255 to 260, furthercomprising a suction-induced flow limiter, an automatic stop/start, atemperature-induced flow limiter, or bite-resistant structural supports.

262. A drug delivery device configured to be removably inserted in apatient's mouth and for continuous or semi-continuous intraoraladministration of a drug, said device comprising:

-   -   (i) a fastener to removably secure said drug delivery device to        a surface of said patient's mouth;    -   (ii) a mechanical pump; and    -   (iii) an oral liquid impermeable drug reservoir containing any        of the pharmaceutical compositions of any one of items 1 to 151,        the volume of said drug reservoir being from 0.1 mL to 5 mL.

263. The drug delivery device of item 262, wherein said mechanical pumpis selected from: a spring, an elastomer, compressed gas, and apropellant.

264. The drug delivery device of any one of items 255 to 263, whereinsaid oral liquid impermeable reservoir comprises one or more of: metalreservoirs, plastic reservoirs, elastomeric reservoirs, metallic barrierlayers, valves, squeegees, baffles, rotating augers, rotating drums,propellants, pneumatic pumps, diaphragm pumps, hydrophobic materials,and hydrophobic fluids.

265. The drug delivery device of any one of items 255 to 264, whereinsaid device is configured such that 4 hours after inserting a drugdelivery device including a fresh reservoir in a patient's mouth andinitiating the administration, less than 5%, 3%, or 1% by weight of anoriginally contained pharmaceutical composition in the reservoirincludes an oral liquid.

266. The drug delivery device of any one of items 255 to 265, furthercomprising a suction-induced flow limiter, an automatic stop/start, atemperature-induced flow limiter, a pressure-invariant mechanical pump,or bite-resistant structural supports.

267. The drug delivery device of any one of items 233 to 238 or items244 to 254, wherein said pump is an electrical pump.

268. The drug delivery device of item 267, wherein said electrical pumpis a piezoelectric pump or an electroosmotic pump.

269. The drug delivery device of item 268, wherein said piezoelectricpump is configured to operate at a frequency of less than about 20,000Hz.

270. The drug delivery device of item 269, wherein said electrical pumpcomprises a motor.

271. The drug delivery device of any one of items 233 to 266, whereinsaid pump is a mechanical pump.

272. The drug delivery device of item 271, wherein said pump is anelastomeric drug pump.

273. The drug delivery device of item 272, wherein said elastomeric drugpump comprises an elastomeric balloon, an elastomeric band, or acompressed elastomer.

274. The drug delivery device of item 271, wherein said pump is aspring-driven pump.

275. The drug delivery device of item 274, wherein said spring-drivenpump comprises a constant force spring.

276. The drug delivery device of item 275, wherein said spring-drivenpump comprises a spring that retracts upon relaxation.

277. The drug delivery device of any one of items 274 or 275, whereinsaid spring-driven pump comprises two coaxial compression springswherein, upon compression, a first spring with a first diameter iswholly or partially nested within a second spring with a second, largerdiameter.

278. The drug delivery device of item 271, wherein said pump is anegative pressure pump.

279. The drug delivery device of item 271, wherein said pump is apneumatic pump.

280. The drug delivery device of item 271, wherein said pump is agas-driven pump.

281. The drug delivery device of item 280, comprising a gas in a firstcompartment and said drug in a second compartment, said gas providing apressure exceeding 1.013 bar.

282. The drug delivery device of any one of items 280 or 281, whereinsaid gas-driven pump comprises a compressed gas cartridge.

283. The drug delivery device of any one of items 280 to 282, whereinsaid pump comprises a gas, the volume of said gas being less than 35% ofthe volume of said pharmaceutical composition.

284. The drug delivery device of any one of items 280 to 283, whereinsaid pump comprises a gas generator.

285. The drug delivery device of item 271, wherein said pump is apropellant-driven pump.

286. The drug delivery device of item 285, wherein said pump comprises aliquid propellant, said liquid propellant having a boiling point of lessthan 37° C. at sea level atmospheric pressure.

287. The drug delivery device of item 286, wherein said liquidpropellant is a hydrocarbon, a halocarbon, a hydrofluoralkane, an ester,or an ether.

288. The drug delivery device of item 287, wherein said liquidpropellant is isopentane, trifluorochloromethane, dichlorofluoromethane,1-fluorobutane, 2-fluorobutane, 1,2-difluoroethane, methyl ethyl ether,2-butene, butane, 1-fluoropropane, 1-butene, 2-fluoropropane,1,1-difluoroethane, cyclopropene, propane, propene, or diethyl ether.

289. The drug delivery device of item 287, wherein said liquidpropellant is 1,1,1,2-tetrafluoroethane,1,1,1,2,3,3,3-heptafluoropropane, 1,1,1,3,3,3-hexafluoropropane,octafluorocyclobutane or isopentane.

290. The drug delivery device of item 287, wherein said propellant isisopentane, trifluorochloromethane, dichlorofluoromethane, or1,1,1,2-tetrafluoroethane.

291. The drug delivery device of any of items 285 to 290, wherein saidpropellant has a vapor pressure of greater than 1.5 bar and less than 10bar at 37° C.

292. The drug delivery device of item 291, wherein said propellant has avapor pressure of greater than 2.0 bar and less than 7 bar at 37° C.

293. The drug delivery device of item 292, wherein said propellant has avapor pressure of greater than 3.0 bar and less than 6 bar at 37° C.

294. The drug delivery device of any of items 285 to 290, wherein (i)said propellant has a vapor pressure of greater than 2.1 bar at 37° C.,and (ii) the average rate of drug delivery increases or decreases byless than ±20% across the atmospheric pressure range between 0.782 barand 1.013 bar.

295. The drug delivery device of item 294, wherein (i) said propellanthas a vapor pressure of greater than 3.2 bar at 37° C., and (ii) theaverage rate of drug delivery increases or decreases by less than ±10%across the atmospheric pressure range between 0.782 bar and 1.013 bar.

296. The drug delivery device of item 294, wherein (i) said propellanthas a vapor pressure of greater than 4.7 bar at 37° C., and (ii) theaverage rate of drug delivery increases or decreases by less than ±6%across the atmospheric pressure range between 0.782 bar and 1.013 bar.

297. The drug delivery device of any of items 285 to 296, comprising arigid metal housing containing said pharmaceutical composition and saidpropellant.

298. The drug delivery device of item 297, wherein said rigid metalhousing comprises titanium.

299. The drug delivery device of any one of items 297 or 298, whereinsaid pharmaceutical composition and said propellant are separated by aflexible and/or deformable diaphragm comprising a metal.

300. The drug delivery device of item 299, wherein said flexible and/ordeformable diaphragm comprises tin or silver.

301. The drug delivery device of any one of items 233 to 290, comprisingtwo or more drug pumps.

302. The drug delivery device of any one of items 233 to 301, comprisingtwo or more drug reservoirs.

303. The drug delivery device of any one of items 233 to 302, whereinsaid drug reservoir is substantially impermeable to oxygen gas.

304. The drug delivery device of any one of items 233 to 303, whereinsaid drug reservoir includes a pharmaceutical composition and saidpharmaceutical composition comprises greater than 33% of the totalvolume of the drug reservoir and pump.

305. The drug delivery device of any one of items 233 to 304, whereinthe total volume of said one or more drug reservoirs and said one ormore drug pumps is less than 5 mL.

306. The drug delivery device of item 305, wherein the total volume ofsaid one or more drug reservoirs and said one or more drug pumps is lessthan 3 mL.

307. The drug delivery device of item 306, wherein the total volume ofsaid one or more drug reservoirs and said one or more drug pumps is lessthan 2 mL.

308. The drug delivery device of any one of items 233 to 307, whereinsaid drug reservoir is a syringe assembly comprising a plunger and abarrel, said plunger being in slidable arrangement with said barrel.

309. The drug delivery device of item 308, wherein said syringe assemblyfurther comprises a seal fitted over said plunger, said seal being incontact with said barrel.

310. The drug delivery device of item 309, wherein said seal is anO-ring.

311. The drug delivery device of item 309 or 310, wherein said barrel,plunger, and/or seal is not wetted by water.

312. The drug delivery device of item 309 or 310, wherein said barrel,plunger, and/or seal is not wetted by oil.

313. The drug delivery device of item 309 or 310, wherein said barrel,plunger, and/or seal is not wetted by oil or by water.

314. The drug delivery device of item 309 or 310, wherein said barrel,plunger, and/or seal is non-wettable by the pharmaceutical compositionof any one of items 1 to 151.

315. The drug delivery device of any one of items 309 to 314, whereinsaid barrel, plunger, and/or seal is formed from or coated with afluoropolymer or fluoroelastomer.

316. The drug delivery device of any one of items 309 to 315, wherein asurface of said barrel, plunger, and/or seal is coated with a lubricant.

317. The drug delivery device of item 316, wherein the solubility ofsaid lubricant in said one or more water-immiscible compounds of thepharmaceutical composition is less than 3% (w/w) at 25° C.

318. The drug delivery device of item 316, wherein the solubility ofsaid lubricant in said water is less than 1% (w/w) at 25° C.

319. The drug delivery device of any one of items 316 to 318, whereinsaid lubricant is a halogenated oil or grease.

320. The drug delivery device of item 319, wherein said halogenated oilor grease has an average molecular mass equal to or greater than about1,000 Daltons.

321. The drug delivery device of item 319 or 320, wherein saidhalogenated oil is a perfluorinated polymer, a chlorofluorinatedpolymer, or a fluorinated polyether.

322. The drug delivery device of any one of items 233 to 317, whereinsaid drug reservoir is a syringe barrel and further comprising adeformable and/or mobile plug separating two compartments of saidsyringe barrel.

323. The drug delivery device of item 322, wherein said deformableand/or mobile plug comprises a perfluorinated, fluorinated, orchlorofluorinated oil or grease.

324. The drug delivery device of item 322 or 323, further comprising apropellant in one of said compartments and said pharmaceuticalcomposition in the other of said compartments.

325. The drug delivery device of any one of items 233 to 324, whereinsaid surface is one or more teeth of the patient.

326. The drug delivery device of item 325, wherein said fastenercomprises a band, a bracket, a clasp, a splint, or a retainer.

327. The drug delivery device of item 326, wherein said fastenercomprises a transparent retainer.

328. The drug delivery device of item 326, wherein said fastenercomprises a partial retainer attachable to fewer than 5 teeth.

329. The drug delivery device according to any one of items 233 to 328,comprising one or more drug reservoirs and one or more pumps, whereinsaid drug reservoirs or said pumps are configured to be worn in thebuccal vestibule.

330. The drug delivery device according to any one of items 233 to 328,comprising one or more drug reservoirs and one or more pumps, whereinsaid drug reservoirs or said pumps are configured to be worn on thelingual side of the teeth.

331. The drug delivery device according to any one of items 233 to,comprising one or more drug reservoirs and one or more pumps, whereinsaid drug reservoirs or said pumps are configured to be wornsimultaneously in the buccal vestibule and on the lingual side of theteeth.

332. The drug delivery device according to any one of items 233 to 328,comprising one or more drug reservoirs and one or more pumps, whereinsaid drug reservoirs or said pumps are configured bilaterally.

333. The drug delivery device according to any one of items 233 to 328,comprising one or more drug reservoirs and one or more pumps, whereinsaid drug reservoirs or said pumps are configured to administer saidpharmaceutical composition into the mouth of said patient on the lingualside of the teeth.

334. The drug delivery device of item 333, comprising a fluidic channelfrom the buccal side to the lingual side of said patient's teeth fordispensing said pharmaceutical composition.

335. The drug delivery device according to any one of items 233 to 328,comprising one or more drug reservoirs and one or more pumps, whereinsaid drug reservoirs or said pumps are configured to administer saidpharmaceutical composition onto the buccal or sublingual mucosa of saidpatient.

336. The drug delivery device of item 335, comprising a tube, channel,or orifice having a distal end positioned proximal to the buccal orsublingual mucosa within a zone bounded in part by a water vapor and gaspermeable membrane that is saliva-repelling.

337. The drug delivery device of any one of items 152 to 336, comprisinga fluidic channel in said fastener through which said pharmaceuticalcomposition is administered into the mouth of said patient.

338. The drug delivery device of item 337, comprising a leak-freefluidic connector for direct or indirect fluidic connection of saidfastener to said one or more drug reservoirs.

339. The drug delivery device of item 337 or 338, comprising a flowrestrictor in said fastener for controlling the flow of saidpharmaceutical composition.

340. The drug delivery device of any one of items 233 to 339, whereinsaid fastener comprises a pump or a power source.

341. The drug delivery device of any one of items 233 to 339, comprisinga tapered flow path for said drug with a taper equal to or less than 60degrees.

342. The drug delivery device of item 341, wherein said tapered flowpath comprises a taper of less than or equal to 45 degrees.

343. The drug delivery device of item 342, wherein said tapered flowpath comprises a taper of less than or equal to 30 degrees.

344. The drug delivery device of any one of items 152 to 343, whereinthe drug reservoir is in fluid communication with a tube, channel, ororifice of less than 4 cm, 3 cm, 2 cm, 1 cm, 0.5 cm, or 0.2 cm in lengthand the dynamic viscosity of the pharmaceutical composition is greaterthan about 1,000 cP, 10,000 cP, or 100,000 cP, and where the device isconfigured to administer said drug via the tube, channel, or orifice.

345. The drug delivery device of item 344, wherein said tube, channel,or orifice has a minimum internal diameter of greater than about 0.1 mm,0.2 mm, 0.3 mm, 0.4 mm, 0.5 mm, 1 mm, 2 mm, 3 mm, 4 mm, or 5 mm.

346. The drug delivery device of item 345, wherein said internaldiameter is greater than about 0.1 mm and less than 1 mm, 0.8 mm, 0.6mm, 0.5 mm, 0.4 mm, 0.3 mm or 0.2 mm.

347. The drug delivery device of any one of items 233 to 345, furthercomprising a flow restrictor that sets the administration rate of saidpharmaceutical composition.

348. The drug delivery device of item 347, wherein the length of saidflow restrictor sets the administration rate of said pharmaceuticalcomposition.

349. The drug delivery device of item 348, wherein said flow restrictoris flared.

350. The drug delivery system of item 347, wherein said flow restrictorcomprises a diameter smaller than 1 mm and larger than 0.05 mm and alength between 0.5 cm and 10 cm.

351. The drug delivery system of item 350, wherein said flow restrictorcomprises a diameter smaller than 0.7 mm and is larger than 0.2 mm.

352. The drug delivery system of item 350, wherein said flow restrictorcomprises a plastic.

353. The drug delivery system of item 352, wherein said plasticcomprises an engineering plastic.

354. The drug delivery system of Item 353, wherein said engineeringplastic comprises a polyamide or a polyester, or a polycarbonate, or apolyetheretherketone, or a polyetherketone, or a polyimide, or apolyoxymethylene, or a polyphenylene sulfide, or a polyphenylene oxide,or a polysulphone, or polytetrafluoroethylene, or polyvinylidenedifluoride, or ultra-high-molecular-weight polyethylene, or a strongelastomer.

355. The drug delivery device of item 347, wherein said flow restrictormay be adjusted by the physician or the patient to set the rate of flow.

356. The drug delivery device of any one of items 152 to 355, whereinsaid drug delivery device is configured to deliver an average hourlyrate of volume of from about 0.015 mL/hour to about 1.25 mL/hour over aperiod of from about 4 hours to about 168 hours at 37° C. and a constantpressure of 1.013 bar, wherein said average hourly rate varies by lessthan ±20% or ±10% per hour over a period of 4 or more hours.

357. The drug delivery device of item 356, wherein said drug deliverydevice comprises oral fluid contacting surfaces that are compatible withsaid oral fluids, such that said average rate of delivery of said drugincreases or decreases by less than ±20% or ±10% per hour after saiddevice is immersed for five minutes in a stirred physiological salinesolution at 37° C. comprising any one of the following conditions: (a)pH of about 2.5; (b) pH of about 9.0; (c) 5% by weight olive oil; and(d) 5% by weight ethanol.

358. A method of treating Parkinson's disease comprising administeringthe pharmaceutical composition of any of items 1 to 114 or 117 to 127 toa patient using the device of any of items 152 to 357.

359. A method of administering a pharmaceutical composition to apatient, said method comprising removably attaching the device of anyone of items 152 to 357 to an intraoral surface of said patient.

360. The method of item 359, further comprising detaching said devicefrom said intraoral surface.

361. The method of item 359 or 360, said method further comprisingadministering said drug to said patient for a delivery period of notless than about 4 hours and not more than about 7 days.

362. The method of item 359, wherein said device comprises a drugreservoir comprising a volume of a drug, and said method furthercomprises oral administration at a rate in the range of from 15 μL perhour to about 1.25 mL per hour during the delivery period.

363. The method of item 359 or 360, wherein the fluctuation index ofsaid drug is less than or equal to 2.0, 1.5, 1.0, 0.75, 0.50, 0.25, or0.15 during the delivery period.

364. The method of item 359 or 360, wherein said method comprises oraladministration at a rate in the range of from about 0.015 mL/hour toabout 0.25 mL/hour.

365. The method of item 359 or 360, wherein said method comprises oraladministration at a rate in the range of from about 0.25 mL/hour toabout 0.5 mL/hour; from about 0.5 mL/hour to about 0.75 mL/hour; or fromabout 0.75 mL/hour to about 1.0 mL/hour.

366. The method of item 359 or 360, wherein said method comprises oraladministration at a rate in the range of from about 1.0 mL/hour to about1.25 mL/hour.

367. The method of any one of items 359 to 362, wherein said devicecomprises a drug reservoir comprising a pharmaceutical compositioncomprising a drug and the drug is administered to said patient at anaverage rate of not less than 0.01 mg per hour and not more than 250 mgper hour.

368. The method of item 367, wherein said drug is administered to saidpatient at an hourly rate in the range of 0.01 mg per hour to 1 mg perhour.

369. The method of item 367, wherein said drug is administered to saidpatient at an hourly rate in the range of 1 mg per hour to 10 mg perhour.

370. The method of item 367, wherein said drug is administered to saidpatient at an hourly rate in the range of 10 mg per hour to 100 mg perhour.

371. The method of item 367, wherein said drug is administered to saidpatient at an hourly rate in the range of 100 mg per hour to 250 mg perhour.

372. The method of any one of items 358 to 371, wherein saidpharmaceutical composition is administered to said patient at least onceevery 60 minutes.

373. The method of item 372, wherein said pharmaceutical composition isadministered to said patient at least once every 30 minutes.

374. The method of item 373, wherein said pharmaceutical composition isadministered to said patient at least once every 15 minutes.

375. The method of any one of items 359 to 371, wherein saidpharmaceutical composition is administered to said patient continuously.

376. The method of any one of items 359 to 375, wherein saidpharmaceutical composition is administered to said patient over adelivery period of 4, 8, 16, 24, or more hours.

377. The method of any one of items 359 to 376 further comprisingtreating a disease in said patient, wherein said disease is mucositis,allergy, immune disease, anesthesia, bacterial infections, cancer, pain,organ transplantation, disordered sleep, epilepsy and seizures, anxiety,mood disorders, post-traumatic stress disorder, arrhythmia,hypertension, heart failure, spasticity, or diabetic nephropathy.

378. The method of any one of items 359 to 376 further comprisingtreating a disease in said patient, wherein said disease is multiplesclerosis, cerebral palsy, spasticity, neurogenic orthostatichypotension, Wilson's disease, cystinuria, rheumatoid arthritis,Alzheimer's disease, Type-1 Gaucher disease, Type C Niemann-Pickdisease, eosinophilic gastroenteritis, chronic mastocytosis, ulcerativecolitis, gastro-oesophageal reflux, gastroenteritis, hyperemesisgravidarum, glioblastoma multiformae, anaplastic astrocytoma, pulmonaryhypertension, coronary heart disease congestive heart failure, angina,Type 2 diabetes, COPD, asthma, irritable bowel syndrome, overactivebladder, and urinary urge incontinence.

379. The method of any one of items 359 to 376 further comprisingtreating a disease in said patient, wherein said disease is myastheniagravis and said pharmaceutical composition comprises pyridostigmine.

380. The method of any one of items 359 to 376, wherein saidpharmaceutical composition comprises one or more drugs selected frommethylphenidate, prostaglandins, prostacyclin, treprostinil, beraprost,nimodipine, and testosterone.

381. The method of any one of items 359 to 380, wherein saidpharmaceutical composition comprises a mucoadhesive polymer.

382. The method of item 381, wherein said pharmaceutical compositionfurther comprises a permeation enhancer.

383. The method of any one of items 359 to 382, wherein saidpharmaceutical composition comprises drug dissolved in an aqueoussolution.

384. The method of item 383, wherein said aqueous solution furthercomprises glycerol, ethanol, propylene glycol, polyethylene glycol (PEO,PEG) or DMSO.

385. The method of any one of items 359 to 384, wherein saidpharmaceutical composition further comprises a thickening agent.

386. The method of item 385, wherein said thickening agent is a sugar, asugar alcohol, or a polymer.

387. The method of item 386, wherein said thickening agent is celluloseor a cellulose derivative.

388. The method of item 386, wherein said thickening agent is selectedfrom carboxymethyl cellulose, microcrystalline cellulose, hyaluronicacid, polyacrylic acid, polymethacrylic acid, alginic acid, or saltsthereof.

389. The method of item 386, wherein said thickening agent is selectedfrom sucrose, glucose, fructose, sorbitol, and mannitol.

390. The method of any one of items 359 to 376, further comprisingtreating Parkinson's disease.

391. A method for treating Parkinson's disease in a patient, said methodcomprising:

(a) inserting the drug delivery device of any one of items 233 to 357into said patient's mouth, said device having a drug reservoircomprising levodopa or a levodopa prodrug;

(b) administering into said patient's mouth said levodopa or a levodopaprodrug for a period of at least 4 hours at an hourly rate in the rangeof 30 mg/hour to 150 mg/hour, such that a circulating plasma levodopaconcentration greater than 1,200 ng/mL and less than 2,500 ng/mL iscontinuously maintained for a period of at least 4 hours during saidadministration; and

(c) removing said drug delivery device from the mouth.

392. The method of item 391 comprising administering into said patient'smouth said levodopa or a levodopa prodrug for a period of at least 8hours at an hourly rate in the range of 30 mg/hour to 150 mg/hour, suchthat a circulating plasma levodopa concentration greater than 1,200ng/mL and less than 2,500 ng/mL is continuously maintained for a periodof at least 8 hours during said administration.

393. A method for treating Parkinson's disease in a patient, said methodcomprising:

(a) inserting a drug delivery device comprising the pharmaceuticalcomposition of any one of items 1 to 113 into said patient's mouth, saidpharmaceutical composition comprising levodopa or levodopa prodrug;

(b) administering into said patient's mouth said levodopa or levodopaprodrug for a period of at least 4 hours at an hourly rate in the rangeof 30 mg/hour to 150 mg/hour, such that a circulating plasma levodopaconcentration greater than 1,200 ng/mL and less than 2,500 ng/mL iscontinuously maintained for a period of at least 4 hours during saidadministration; and

(c) removing said drug delivery device from the mouth.

394. The method of item 393 comprising administering into said patient'smouth said levodopa or levodopa prodrug for a period of at least 8 hoursat an hourly rate in the range of 30 mg/hour to 150 mg/hour, such that acirculating plasma levodopa concentration greater than 1,200 ng/mL andless than 2,500 ng/mL is continuously maintained for a period of atleast 8 hours during said administration.

395. The method of item 393 or 394, wherein the fluctuation index oflevodopa is less than or equal to 2.0, 1.5, 1.0, 0.75, 0.50, 0.25, or0.15 for a period of at least 4 hours during said administration.

396. The method of item 395, wherein the fluctuation index of levodopais less than or equal to 2.0, 1.5, 1.0, 0.75, 0.50, 0.25, or 0.15 for aperiod of at least 8 hours during said administration.

397. The method of any one of items 393 to 396, wherein during saidadministration the circulating levodopa plasma concentration varies byless than +/−20% or +/−10% from its mean for a period of at least 1, 2,or 4 hours.

398. A method for treating Parkinson's disease in a patient, said methodcomprising continuous or semi-continuous administration of thepharmaceutical composition of any one of items 1 to 114 or 117 to 127into said patient at a rate of 10 mg/hour to 200 mg/hour for a period ofabout 4 hours to about 168 hours.

399. The method of any one of items 391 to 398, wherein said method oftreating Parkinson's disease comprises treating a motor or non-motorcomplication of Parkinson's disease.

400. The method of item 406, wherein said motor or non-motorcomplication comprises tremor, akinesia, bradykinesia, dyskinesia,dystonia, cognitive impairment, or disordered sleep.

401. A method of treating Parkinson's disease in a patient comprisingadministering the pharmaceutical composition of any of items 1 to 114 or117 to 127 to a patient using the method of any of items 359 to 375 or391 to 400.

402. A method of preparing a pharmaceutical composition comprising fromabout 35% (w/w) to about 70% (w/w) of a drug comprising levodopa and/orcarbidopa; said composition comprising a surfactant, an oil, and water;said composition, when at 37° C., comprising solid particles of saiddrug; said drug having a partition coefficient in favor of water; saidsurfactant being present in an amount sufficient to render saidcomposition physically stable; and said method comprising contacting anaqueous solution comprising said surfactant and water with solidparticles of said drug, to produce a mixture of said solid particles insaid aqueous solution.

403. The method of item 402, further comprising contacting said mixturewith said oil.

404. A method for treating Parkinson's disease in a subject, said methodcomprising:

(a) inserting a drug delivery device into said subject's mouth, saiddevice having (i) a fastener to removably secure said drug deliverydevice to a surface of said patient's mouth; (ii) an electrical ormechanical pump; and (iii) an oral liquid impermeable drug reservoirhaving a volume of from 0.1 ml to 5 ml comprising a suspension or solidcontaining levodopa or a levodopa prodrug;

(b) administering into said patient's mouth said levodopa or a levodopaprodrug continuously or semi-continuously; and

(c) removing said drug delivery device from the mouth of the subject,wherein said subject has a score of 4 and 5 on the Hoehn and Yahr scale.

405. The method of item 404, wherein step (b) comprises administeringinto said subject's mouth said levodopa or a levodopa prodrugsemi-continuously at a frequency of at least once every 30 minutes.

406. The method of item 404 or 405, wherein the suspension or solid isadministered to the subject for a period of at least 8 hours at anhourly rate in the range of 10-125 mg/hour, such that a circulatingplasma levodopa concentration greater than 1,200 ng/m L and less than2,500 ng/mL is continuously maintained for a period of at least 8 hoursduring said administration.

407. The method of any one of items 404 to 406, wherein the subject hasdelayed gastric emptying or retarded gastrointestinal transit.

408. The method of any one of items 404 to 407, wherein the drugreservoir comprising a composition comprising a suspension that is adrug particle-containing emulsion comprising (i) from 35% to 70% (w/w)drug particles comprising levodopa and/or carbidopa, or salts thereof,(ii) from 19% to 30% (w/w) of one or more water-immiscible compounds,(iii) from 2% to 16% (w/w) water, and (iv) from 1% to 8% (w/w)surfactant.

409. The method of item 408, wherein the suspension comprises acontinuous hydrophilic phase comprising greater than 50% (w/w) drugparticles.

410. The method of any one of items 404 to 409, wherein the drugdelivery device comprises an automatic stop/start.

411. The method of any one of items 404 to 409, wherein the drugdelivery device comprises a suction-induced flow limiter.

412. The method of any one of items 404 to 409, wherein the drugdelivery device comprises a temperature-induced flow limiter.

413. The method of any one of items 404 to 409, wherein the drugdelivery device comprises bite-resistant structural supports.

414. A method for treating spasticity in a subject, said methodcomprising:

(a) inserting a drug delivery device into said subject's mouth, saiddevice having (i) a fastener to removably secure said drug deliverydevice to a surface of said patients mouth; (ii) an electrical ormechanical pump; and (iii) an oral liquid impermeable drug reservoirhaving a volume of from 0.1 ml to 5 ml comprising a suspension or solidcontaining baclofen;

(b) administering into said patient's mouth said baclofen continuouslyor semi-continuously; and

(c) removing said drug delivery device from the mouth of the subject.

415. A method for treating myasthenia gravis in a subject, said methodcomprising:

(a) inserting a drug delivery device into said subject's mouth, saiddevice having (i) a fastener to removably secure said drug deliverydevice to a surface of said patients mouth; (ii) an electrical ormechanical pump; and (iii) an oral liquid impermeable drug reservoirhaving a volume of from 0.1 ml to 5 ml comprising a solution orsuspension of pyridostigmine;

(b) administering into said patient's mouth said pyridostigminecontinuously or semi-continuously; and

(c) removing said drug delivery device from the mouth of the subject.

416. A method for treating disease in a subject suffering from delayedgastric emptying or retarded gastrointestinal transit, the methodincluding:

(a) inserting a drug delivery device into the subjects mouth, the devicehaving (i) a fastener to removably secure the drug delivery device to asurface of the patient's mouth; (ii) an electrical or mechanical pump;and (iii) an oral liquid impermeable drug reservoir having a volume offrom 0.1 ml to 5 ml including a suspension or solid containing a druguseful for treating said disease;

(b) administering into the patient's mouth the drug continuously orsemi-continuously at a frequency of at least once every 30 minutes; and

(c) removing the drug delivery device from the mouth of the subject.

417. The method of item 416, wherein an efficacious circulating plasmaconcentration of the drug is continuously maintained for a period of atleast 8 hours during the administration.

418. The method of item 416 or 417, wherein the drug delivery deviceincludes an automatic stop/start, a suction-induced flow limiter, atemperature-induced flow limiter, and/or bite-resistant structuralsupports.

419. A drug delivery device configured for continuously orsemi-continuously administering a drug into the mouth of a patient, saiddrug delivery device comprising:

(i) a pharmaceutical composition comprising a paste, solution orsuspension having a viscosity greater than 100 poise and less than500,000 poise at 37° C. and comprising said drug; and

(ii) a mechanical pump comprising a flow restrictor, said flowrestrictor comprising an internal diameter between 0.05 mm and 3.00 mmand a length between 0.25 cm and 20 cm, configured and arranged toadminister said pharmaceutical composition at a rate between 0.001mL/hour and 1.25 mL/hour.

420. The drug delivery device of item 419, wherein said mechanical pumpcomprises a propellant.

421. The drug delivery device of item 420, wherein said propellant has avapor pressure at about 37° C. greater than 1.2 bar and less than 50bar.

422. The drug delivery device of item 419, wherein said pharmaceuticalcomposition comprises solid drug particles and/or excipient particleshaving a D₉₀ between 0.1 μm and 200 μm and a D₅₀ between 0.1 μm and 50μm when measured by light scattering with the particles dispersed in anon-solvent.

423. The drug delivery device of item 420, wherein said device isconfigured such that:

(i) said administration rate is greater than 0.03 mL/hour and less than0.5 mL/hour;

(ii) said viscosity is greater than 200 poise and less than 100,000poise;

(iii) said flow restrictor has an internal diameter between 0.1 mm and0.7 mm and a length between 1 cm and 5 cm; and

(iv) said propellant has a vapor pressure at about 37° C. greater than2.5 bar and less than 15 bar.

424. The drug delivery device of item 429, wherein said solid drugparticles and/or excipient particles having a D₉₀ between 1 μm and 50 μmand a D₅₀ between 0.5 μm and 30 μm when measured by light scatteringwith the particles dispersed in a non-solvent.

425. The drug delivery device of item 423, wherein said device isconfigured such that:

(i) said administration rate is greater than 0.05 mL/hour and less than0.2 mL/hour;

(ii) said viscosity is greater than 500 poise and less than 75,000poise;

(iii) said flow restrictor has an internal diameter between 0.2 mm and0.5 mm and a length between 1 cm and 2.5 cm; and

(iv) said propellant has a vapor pressure at about 37° C. greater than 4bar and less than 10 bar.

426. The drug delivery device of item 425, wherein said solid drugparticles and/or excipient particles having a D₉₀ between 3 μm and 30 μmand a D₅₀ between 2 μm and 20 μm when measured by light scattering withthe particles dispersed in a non-solvent.

427. A method of administering a pharmaceutical composition to apatient, said method comprising:

(i) inserting said drug delivery device into the mouth of said patient;

(ii) continuously or semicontinuously administering said pharmaceuticalcomposition into the mouth of a patient using at a rate between 0.001mL/hour and 1.25 mL/hour;

(iii) wherein said pharmaceutical composition comprises a paste,solution or suspension having a viscosity greater than 100 poise andless than 500,000 poise at 37° C.; and

(iv) said drug delivery device comprises a mechanical pump comprising aflow restrictor comprising an internal diameter between 0.05 mm and 3.00mm and a length between 0.25 cm and 20 cm.

428. The method of item 427, wherein said mechanical pump comprises apropellant, said propellant having a vapor pressure at about 37° C.greater than 1.2 bar and less than 50 bar.

429. The method of item 427, wherein said solid drug particles and/orexcipient particles having a D₉₀ between 0.1 μm and 200 μm and a D₅₀between 0.1 μm and 50 μm when measured by light scattering with theparticles dispersed in a non-solvent.

430. The method of item 428, wherein:

(i) said administration rate is greater than 0.03 mL/hour and less than0.5 mL/hour;

(ii) said viscosity is greater than 200 poise and less than 100,000poise;

(iii) said flow restrictor has an internal diameter between 0.1 mm and0.7 mm and a length between 1 cm and 5 cm; and

(iv) said propellant has a vapor pressure at about 37° C. greater than2.5 bar and less than 15 bar.

431. The method of item 430 wherein said solid drug particles and/orexcipient particles having a D₉₀ between 0.1 μm and 50 μm and a D₅₀between 0.5 μm and 30 μm when measured by light scattering with theparticles dispersed in a non-solvent.

432. The method of item 431 wherein:

(i) said administration rate is greater than 0.05 mL/hour and less than0.2 mL/hour;

(ii) said viscosity is greater than 500 poise and less than 75,000poise;

(iii) said flow restrictor has an internal diameter between 0.2 mm and0.5 mm and a length between 1 cm and 2.5 cm; and

(iv) said propellant has a vapor pressure at about 37° C. greater than 4bar and less than 10 bar.

433. The method of item 432 wherein said solid drug particles and/orexcipient particles having a D₉₀ between 3 μm and 30 μm and a D₅₀between 2 μm and 20 μm when measured by light scattering with theparticles dispersed in a non-solvent.

The following examples are meant to illustrate the invention. They arenot meant to limit the invention in any way.

Example 1. Preparation and Extrusion of a 157 mg/mL CD (0.74 M) and 629mg/mL (3.19 M) LD Solid Particle Containing Suspension, Comprising Only464 mg/mL of a Carrier Fluid Made of Oil, Water and Surfactant that isPhysically Stable and is Also Resistant to Air-Oxidation for a Month,Appropriate for Extrusion into the Mouth

Ingredients: LD (D₅₀ about 75 μm; D₉₀ about 200 μm); CD (D₉₅ about 100μm, D₈₀ about 45 μm); Kolliphor RH 40 (from Sigma); Miglyol 812 (PeterCremer, Cincinnati, Ohio); de-ionized water.

0.8 g Kolliphor RH 40 also known as Cremophor RH 40 was dissolved bywarming and agitation in 1.5 g water. 2.4 g CD and 9.6 LD was added andthe mixture was homogenized, then allowed to age for 10 hours withperiodic mixing. 4.75 g of Miglyol 812, a medium chain triglyceride, wasadded, the suspension was homogenized and allowed to age for 3 hourswith periodic mixing.

Most of the LD and most of the CD was particulate, i.e., most of the LDand the CD was suspended, not dissolved. The suspension of the soliddrug particles was deformable but could not be poured at the ambienttemperature of about 23±2° C. The suspension was soft, compliant, easyto mechanically deform and it retained its shape upon deformation. Afterstorage for a month at 23±2° C. there was no visible indication ofsedimentation of solid drug particles, nor was there any visibleindication of phase separation of the oil and the water, i.e., thesuspension remained unchanged and appeared homogeneous after storage fora month. The suspension was off-white, nearly colorless, and it wasnearly tasteless, i.e., it did not have a strong or unpleasant taste.

The calculated approximate volume of the suspension in the absence oftrapped air was about 15.3 mL and the measured weight was 19.05 g. Fromthese values a density of about 1.25 g/mL is calculated, providing, ifall or most air were removed, a suspension with a CD concentration ofabout 157 mg/mL and with an LD concentration of about 629 mg/mL.

Although it was not removed, any trapped air could have been removed forexample by centrifugation, or by chilling to a temperature where thepartial pressure of water is low, e.g., less than 10° C., for exampleabout 0° C., and pulling a vacuum.

About 6.5 g of the soft suspension was loaded in a 20 mL Crn® CRONO®syringe (sold by CANE S.p.A, Rivoli, Italy) equipped with a luer lock.The visible bubbles of trapped air were moved by hard tapping against arubber pad, which raised them to the orifice where they were expelledwith some of the suspension by applying pressure to the plunger. Theremaining volume was about 5 mL and the weight was about 6 g for anapparent density of about 1.2 g/mL. The suspension was extruded as aplug through a 25 mm long 16 gauge nozzle, i.e., a nozzle having aninner diameter of 1.29 mm and a cross sectional area of 1.31 mm². Thenozzle through which the suspension was extruded had a female luer forattachment to the male luer of the syringe. In plug flow, known also asslip flow, a deformable plug may be extruded through an orifice byslipping through it, slip-flow accounting for at least some of the flow.The suspension-containing syringe having the attached nozzle was loadedin a CRONO PAR (Rivoli, Italy) pump. The pump was set to delivercontinuously a volume of 0.1 mL/hour.

The suspension in the syringe was extruded through the nozzle at about23±2° C. The extrudate was a long cylindrical fiber that retained itsshape for more than 10 hours after its extrusion at ambient temperature.The extruded fiber was off-white, nearly colorless, and remainedcolorless when air-exposed at ambient temperature for more than a week,showing that the oxidations of CD and LD to colored degradation productswere slow, i.e., that the suspension was substantially stable toair-oxidation for a week. This in contrast with a saturated aqueoussolution of the LD and CD which turns dark under air in 24 hours.

The change of the extrudate weight, as a function of extrusion time, isshown in Table 3. When the extrusion ended the pump signaled that thesyringe was empty, i.e., that about all of the suspension was extruded.The pump did not signal, at any time, an occlusion.

TABLE 3 Change in extrudate weight with extrusion time. Extrusion timeExtruded weight (hrs) (g) 0 0 8.92 0.93 20.07 2.19 30.08 3.31 36.95 4.1143.45 4.87 45.4 5.07

The slope of the plotted data, which would equal the extrudate densityif the pump extruded at the set rate of 0.1 mL/hour, was about constantat about 1.12 g/mL for the about 45 hour long extrusion period. Theobserved density was less than the above estimated density of about 1.2g/mL, suggesting that the actual pumping rate of the Crono Par pump,when set at 0.1 mL/hour, was only about 0.093 mL/hour and/or that waterevaporated from the ambient air exposed extrudate.

The constancy of the density shows that the concentration of theextrudate during the 45 hour long extrusion remained constant in spiteof the LD and CD solid particles having estimated densities of about 1.5g/mL, which is considerably higher than the 0.97 g/mL density of thecarrier fluid.

Example 2. Showing the Advantage of Adding Oil to the Carrier Fluid andthat without Oil the Suspension is not Physically Stable

Ingredients: LD, CD, Kolliphor RH 40 and de-ionized water all as inExample 1.

0.8 g Kolliphor RH 40 was dissolved by warming in 6.5 g water at about60° C.; the calculated volume of the solution is about 7.26 mL; 2.4 g CDand 9.6 LD (estimated combined volumes of the two drugs, 8 mL) was addedand the mixture was homogenized. As in Example 1, most of the LD andmost of the CD was particulate, not dissolved. The respectiveconcentrations of CD and LD in the resulting suspension were 157 mg/mLand 629 mg/mL, similar to those in Example 1.

Unlike the suspension of Example 1, which was not pourable at about23±2° C., the suspension without oil was pourable; it could be pouredand was, unlike the suspension of Example 1, homogenized by shaking. Anearly clear, particle-free liquid layer was observed at the top in thesuspension after about an hour, unlike in the oil-containing suspensionof Example 1 where there was no sedimentation or any other indication ofinhomogeneity after a month of storage at about 23±2° C. The clear layerbecame thicker after 3 hours.

Use of the suspension made without oil would require frequentre-suspension (e.g., by shaking), unlike the physically stableoil-containing suspension.

Example 3. Preparation and Extrusion of a Physically Stable 156 mg/mL(0.74 M) CD and 624 mg/mL (3.16 M) LD Containing Suspension ComprisingOnly 460 mg/mL of a Carrier Emulsion, Made with a Food-Grade Oil,Suitable for Infusion in the Mouth

Ingredients: All as in Example 1, except for the canola oil (SafewayKitchens, distributed by Safeway, Pleasanton, Calif.) which replaced theMiglyol 812.

Most of the LD and most of the CD were particulate, i.e., were notdissolved. The composition was similar to that of Example 1, except that4.7 g of canola oil (density about 0.92 g/mL) was used instead of 4.75 gof Miglyol 812 (density about 0.95 g/mL).

To prepare the suspension, 0.8 g Kolliphor RH 40 was dissolved bywarming and agitation in 1.5 g water. 2.4 g CD and 9.6 LD was added andthe mixture was homogenized, then allowed to age with periodic mixingfor 4 hours. 4.7 g of canola oil was added, the suspension wasre-homogenized by mixing and allowed to age for 3 hours with periodicmixing. The resulting suspension was plastically deformable, retainingits shape upon deformation. Although it was not pourable at the ambienttemperature of about 23±2° C., it was soft, compliant and it was easy tomechanically deform and as seen below easy to extrude through the belowdescribed nozzle as a plug. After a month, there was no visibleindication of sedimentation of the solid drug particles, nor was thereany visible indication of phase separation of the oil and the water. Thesuspension remained unchanged, i.e., homogeneous, after storage for amonth at about 23±2° C. The suspension remained off-white, showing thatits rate of air-oxidation was much slower than that of dissolved LD orCD. The suspension was nearly tasteless, i.e., it did not have a strongor unpleasant taste.

The estimated density of the suspension in the absence of trapped airand assuming that the densities of LD and of CD are of about 1.5 g/mLwas about 1.24 g/mL and the respective CD and LD concentrations were 156mg/mL and 624 mg/mL. Trapped air should be possible to remove, e.g., bycentrifugation or by chilling to a temperature where the partialpressure of water is low, e.g., less than 10° C., for example about 0°C., and pulling a vacuum.

About 5 g of the soft suspension were loaded in a 20 mL Crn® CRONO®syringe having a male luer. Air bubbles were visible; some of the largerone could be moved to the orifice and were expelled with some of thesuspension by moving the piston back and forth while the syringe wascapped, and by hard tapping then applying pressure to the plunger toexpel the layer containing the visible air bubbles. The remaining volumewas about 4.5 mL.

The syringe was loaded in a CRONO PAR pump, set to deliver continuouslya volume of 0.1 mL/hour, and extruded through a 25 mm long 16 gauge(1.29 mm diameter, about 1.31 mm² cross sectional area) nozzle equippedwith a female luer for attachment to the syringe. The extrudate was along cylindrical fiber that retained its shape for more than 10 hoursafter its extrusion at the ambient temperature, about 23±2° C. The colorof the extruded fiber was off-white and it remained off-white whenair-exposed at ambient temperature for more than a week, showing thatthe oxidations of CD and LD to colored products were slow.

The extruded suspension weight is shown as a function of extrusion timein Table 4. When the extrusion ended the pump signaled that the syringewas empty, i.e., that about all of the suspension was extruded. The pumpdid not signal, at any time, an occlusion.

TABLE 4 Change in extruded weight with extrusion time. Extrusion timeExtruded weight (hrs) (g) 0 0 4.3 0.48 14 1.54 19.28 2.09 26 2.8 37.613.98 42.23 4.46

When plotted in a graph, the slope (equal to the extrudate densityassuming that the pump extrudes 0.1 mL/hour) was about 1.06 g/mL. Thepump set at 0.1 mL/hr may have, however, extruded only 0.093 mL/hr, asestimated in Example 1. In this case the extrudate density would beabout 1.14 g/mL, less than the estimated density of 1.24 g/mL,suggesting trapped air residue and/or evaporation of water during theextrusion. The slope was about constant for the about 42 hour longextrusion period, showing that the concentrations of the densecomponents of the suspensions, CD and of LD, are about constant.

Example 4. Showing that Both Oil and Water are Required for PhysicalStability to Prevent Sedimentation and Caking Upon Extrusion of an 837mg/mL (4.25 M) LD Suspension

Ingredients: LD (sieved particles passing 125 μm openings, not passing32 μm openings); canola oil (as in Example 3); Polysorbate 60 (as inExample 1); de-ionized water.

(a) Example Showing the Requirement for Water in the Carrier EmulsionUsed to Suspend the LD Particles.

An about 837 mg/mL LD suspension in oil was prepared as follows: 1.95 gof Polysorbate 60 was dissolved in 20 g of canola oil. The resultingsolution was clear. 5 g of the solution were homogenized with 10 g of LDto form a soft and viscous suspension that remained unchanged afterstanding for 3 days at 23±2° C.; there was no sedimentation of the densedrug particles, nor did the oil separate from the water; the suspensionremained homogeneous. Most of the LD was particulate, i.e. it was notdissolved.

Part of the suspension was loaded into a 20 mL Crn® CRONO® syringebarrel, then pushed through its >2 mm diameter outlet, to which noflow-restricting nozzle or tubing was attached, by manually applyingpressure on the piston. Unlike the extruded suspensions of Examples 1and 3, or the also extruded, below-described, water and oil containingsuspension of this Example, the delivered suspension did not retain itsshape. Furthermore, the concentration of strongly light-scattering solidparticles visibly changed. The delivered suspension changed from asolid-rich, intensely light scattering suspension to a less lightscattering, more oil-containing suspension; then only nearly clear oilwas delivered with few light scattering solid drug particles. Afterpushing part of the suspension through the opening, it becameincreasingly difficult to push through more. After about half of thesuspension was delivered it became impossible to manually push throughany of the remaining suspension. When the syringe was disassembled,i.e., when its piston was pulled out, a dense and hard solid-rich cakewas found near the outlet of the syringe. This cake filtered, i.e.,retained, the solid drug particles, but passed the nearly particle-freeoil.

The experiment shows that at about 837 mg/mL LD concentration asuspension of solid drug particles of about 32-125 μm size in asurfactant-containing oil, not containing water, changes its compositionduring delivery and that it is difficult or impossible to deliver theentire volume of suspension in a reservoir through an about 2 mmdiameter orifice.

(b) Example Showing the Requirement of Water in the Carrier EmulsionUsed to Suspend the LD Particles.

1.22 g of Polysorbate 60 was dispersed in 12.2 g of water; thePolysorbate 60 was dispersed, but was not dissolved. To 5 g of thedispersion 10 g of LD was added. The resulting suspension was fluid,i.e. it could be poured. Sedimentation of drug particles was observedafter about 30 min; shaking re-homogenized the suspension.

(c) Example Showing Improved Physical Stability of a LD SuspensionContaining Both Oil and Water

10 g of the suspension of part (a) above was mixed with 10 g of thesuspension of part (b) above to form an 837 mg/ml LD suspensioncontaining both oil and water. At about 23±2° C. the suspension wasnon-pourable. It was, however, plastically deformable and retained itsshape upon deformation. When force was applied, it extruded through anozzle as a plug. Unlike in the suspension of part (b) of this example,that did not contain oil and in which sedimentation was observed after30 min, there was no visible sedimentation nor was there any visibleindication of phase separation of the oil and the water after a month;the suspension remained unchanged, i.e., homogeneous, after storage fora month at about 23±2° C.

The suspension was then loaded into a 20 mL Crn® CRONO® syringe. Unlikethe suspension of part (a) the suspension was easy to push through the˜2 mm syringe outlet by applying manual pressure on the piston. Alsounlike the suspension of part (a) the suspension emerging from theopening retained its shape and did not visibly change throughoutdelivery; furthermore no delivery-blocking cake formed, i.e., all of thesuspension in the syringe was delivered.

Next, 4.2 g of the suspension was re-loaded in a Crn® CRONO® syringe, towhich ½ inch long 17 gauge nozzle was attached. The syringe was theninserted in the Crono Par pump. The pump was set for continuous deliveryat 0.12 mL/hour rate and the suspension was extruded for about 18 hours,after which the pump occluded.

The example shows that compositional changes of an about 837 mg/mL,i.e., about 4.2 M, LD suspension can be reduced when the suspensioncomprises oil, water and a surfactant.

Example 5. Showing 87 Hour Long Continuous Extrusion of a 777 mg/mL (3.9M) LD Suspension Made with 32 μm-125 μm LD Particles

Ingredients: Polysorbate 60 (Fluka, Sigma Aldrich Catalog #95754-F); LDparticles (passing 125 μm sieve and not passing 32 μm sieve); canola oil(Safeway Kitchens, distributed by Safeway, Pleasanton), CA; de-ionizedwater.

2.56 g of Polysorbate 60 was dissolved in 12.34 g of canola oil. Thesolution was allowed to stand for 24 hours before use; it was nearlycolorless and transparent. 9.33 g of the solution was mixed with 20 g ofLD, 2.5 mL water was added the mixture was stirred until it washomogeneous. The resulting suspension weighed 31.8 g. It contained 1.6 gPolysorbate 60; 7.73 g canola oil; 2.5 g water and 20 g LD. Itscalculated volume is 25.7 mL assuming absence of trapped air and 1.5g/mL density of LD. The calculated volume and measured weight providedan estimated density of about 1.24 g/mL and an LD concentration of 777mg/mL. Most of the LD was particulate, i.e., it was not dissolved.

The suspension was aged for about 65 hours. It was plasticallydeformable, retained its shape upon deformation, and was not pourable atthe ambient temperature of about 23±2° C. It was soft, compliant, easyto mechanically deform, and easy to squeeze through a 16 gauge 25 mmlong nozzle. When force was applied, it extruded through the nozzle as aplug. Stirring released the largest trapped air bubbles, but smaller airbubbles remained.

About 10 mL of the suspension weighing about 11.6 g were transferred toa 20 mL Crn® CRONO® syringe. Part of the remaining air bubbles wereremoved by intensely shaking the upright reservoir and squeezing out thetopmost layer of the air bubble-rich suspension along with somesuspension, leaving about 8.7 g suspension in the syringe. The residualtrapped air was not removed, but it could be removed by, e.g.,centrifugation, or chilling to a temperature where the partial pressureof water is low (e.g., less than 10° C., for example about 0° C.) andpulling a vacuum.

A 25 mm long 16 gauge stainless steel nozzle with a female Luer wasattached to the syringe and extrusion was started with the Crono Parpump set to deliver 0.1 mL/hour. All of the suspension in the syringewas extruded, i.e., the pump did not occlude. Table 5 below provides theextrusion duration dependence of the weight of the extrudate.

TABLE 5 Change in extrudate weight with extrusion time. Extrusionduration Extrudate weight (hrs) (g) 0 0 11.1 1.16 19.5 2.04 26.6 2.8135.43 3.78 44.53 4.76 50.3 5.36 60.35 6.48 69.68 7.51 87.78 9.36

When plotted in a graph, the slope (which is also the density of theextrudate at the ambient extrusion temperature) is about constant atabout 1.07 g/mL. From Example 1 it appears that when the pump is set fora 0.1 mL/hour delivery rate the actual delivery rate is only 0.093mL/hour, such making the actual delivered density about 1.15 g/mL. Thedensity is constant within less than about ±3%, apparently less thanabout 2%. The lesser than the 1.24 g/mL calculated density is attributedto trapped air and/or water evaporation from the extrudate.

Over 11 days there was no visible sedimentation or phase separation; norwas there cake formation or notable inhomogeneity in the about 87 hoursof extrusion through a 16 gauge, 25 mm long nozzle at a nominal deliveryrate of 0.1 mL/hour. The initially off-white air-exposed suspensionturned light grey, suggesting very slow air-oxidation of the LD.

Example 6. Preparation and Extrusion of a 790 mg/mL Small Particle SizeLD Suspension

Ingredients: Polysorbate 60, (Fluka, Sigma Aldrich Catalog #95754-F); LD(Ajinomoto, jet milled to <10 μm particle size, most of the mass beingof 1-5 μm diameter (see scanning electron micrograph below)); canola oil(Safeway Kitchens, distributed by Safeway, Pleasanton, Calif.);de-ionized water.

100 g of Ajinomoto LD was jet milled using a Glen Mills Jet Mill, set at105 psi supply line, 100 psi grinding line, 80 psi feed push line andfeed rate about 7 g per 20 minutes. Yield: 86 g. 1.16 g of Polysorbate60 was dissolved in 7.7 g canola oil. FIGS. 21A and 21B are micrographsdepicting LD particles formed by jet milling.

20 g of the jet-milled LD was added and the mixture was stirred until itwas homogeneous, then 2.5 g water was added and the mixture was againstirred until it was homogeneous. The resulting suspension was much moreviscous than bread-making dough and its manual mixing was difficult.Most of the LD was particulate, i.e., it was not dissolved. Thecalculated volume of its 31.4 g mass, assuming 1.5 g/mL LD density, is25.31 mL in absence of trapped air. The trapped air was not removed, butit can be removed, e.g., by centrifugation, or by chilling to atemperature where the partial pressure of water is low (e.g., less than10° C., for example about 0° C.) and pulling a vacuum. The calculated LDconcentration in the absence of trapped air is 790 mg/mL (4 M) and theestimated density is 1.24 g/mL.

The suspension was extremely viscous, much more viscous than honey atambient temperature. It was not pourable at the ambient temperature ofabout 23±2° C., but it was soft, compliant, easy to mechanically deform,and easy to squeeze through a 2.4 mm internal diameter 28 cm longtubing. It plastically deformed when force was applied and was extrudedthrough the tubing as a plug.

The Crono Par pump was set for continuous delivery at 1 mL/hour deliveryrate, and a 28 cm long 2.4 mm internal diameter plastic tubing wasattached to the luer of its syringe and filled with the suspension. Thesuspension was then extruded through the tubing for about 20 hours, atthe end of which the syringe was empty. The weight of the extrudate was27.9 g. The extrudate retained its cylindrical shape, i.e., it was anabout 2.4 mm diameter string.

Example 7. Showing that a 570 mg/mL (2.89 M) Suspension of SmallParticle Size LD in Canola Oil without Surfactant and without WaterBecomes Inhomogeneous Upon Extrusion

Ingredients: LD jet milled as in Example 6; canola oil (SafewayKitchens, distributed by Safeway, Pleasanton, Calif.).

About 3.7 g of the jet milled LD (see Example 6) was homogenized bymixing in a 20 mL Crn® CRONO® syringe with about 3.72 g of canola oil.An easy to stir and just barely pourable suspension was formed. Most ofthe LD was particulate, i.e., it was not dissolved. The estimated volumeof the suspension, assuming an about 1.5 g/mL density for LD, was about6.5 mL, the calculated LD concentration was about 570 mg/mL, and thecalculated density was about 1.15 g/mL. Using a Crono PAR pump, and witha 2.4 mm inner diameter, 28 cm long plastic tubing coupled to the luerof the syringe the suspension was pumped at a rate of 1 mL/hour.Filtering, resulting in oil with fewer LD particles being extruded, wasobserved after 1 hour. After 2 hours mostly clear oil was flowing andthe pump occluded. A hard cake of solid particle was found when thesyringe was disassembled. The cake, consisting mostly of LD and littleoil, weighed about 5 g (i.e., about 2 g of oil and only about 0.4 g ofLD were delivered). The estimated amount of LD in the cake was about 3.3g. The experiment showed cake formation, filtering and occlusion duringdelivery in the absence of water and surfactant.

Example 8. Showing that Adding a Surfactant to a 600 mg/mL (3 M)Suspension of Small Particle Size LD in Oil Delays but does not PreventCaking, Filtration and Occlusion Upon Delivery

Ingredients: Polysorbate 60, LD (jet milled as in Example 6), canolaoil.

0.25 g Polysorbate 60 was dissolved in about 2.9 g of canola oil, andthen 3.3 g LD was added. The mixture was homogenized by mixing in thebarrel of a 20 mL Crn® CRONO® syringe. The volume of the resultingsuspension was about 5.5 mL and the LD concentration was about 600mg/mL. The suspension was easy to stir and viscous. The LD was mostlyparticulate, i.e., not dissolved.

Using a Crono PAR pump with a 2.4 mm inner diameter, 28 cm long plastictubing coupled to the luer of its suspension-containing syringe, thesuspension was pumped at flow rate of 3 mL/hour for about 30 min, thenfor 3 hours at 1 mL/hour. The delivered suspension was inhomogeneous,with clear oil being pumped periodically. The pump signaled occlusion,but only after about 4 mL were delivered, i.e., when about 1 mL wasleft. Comparison with the delivery of the suspension of Example 7 showsthat adding Polysorbate 60 was beneficial. In the absence of added watercake formation, filtering and occlusion during delivery were retardedbut were not prevented.

Example 9. Showing that a 541 mg/mL (2.75 M) Suspension of LD Particlesin Surfactant Containing Oil is not Physically Stable; Also Showing thatAdding a Small Amount of Water to the Unstable Suspension Produces a 477mg/mL (2.4 M) Physically Stable Non-Sedimenting and ExtrudableSuspension; Also Showing that Trapped Air can be Removed from theSuspension by Centrifugation; and Additionally Showing that theContinuous Phase in the Carrier Fluid of the Stable Suspension isAqueous, Even Though it Contains Much More Oil than Water

Ingredients: LD (95 weight % of the particles passing 250 μm sieveopenings and about 30 weight % passing 125 μm sieve openings); canolaoil; Polysorbate 60; de-ionized water.

Most of the LD was particulate, i.e., not dissolved.

(a) 1.2 g Polysorbate 60 was dissolved in 12 g of canola oil. 12 g of LDwas added and the mixture was ground in a mortar until it washomogeneous. The resulting suspension of about 541 mg/mL (2.75 M) LDconcentration was transferred to a glass vial. After 4 hours a clear oillayer was observed on the top of the suspension; after 12 hours thethickness of the clear oil layer increased three-fold, indicatingsedimentation and showing that the suspension not physically stable.

(b) The unstable 541 mg/mL suspension was returned to the mortar, 2 g ofwater was added, and the suspension was re-ground for 15 min. The waterhardened the suspension; 1 g more water was added, for a total of 3 gand grinding was resumed for 20 min. The adding of water andhomogenizing by grinding resulted in a soft, mechanically compliant,homogeneous suspension in which the concentration of LD was about 477mg/mL (2.4 M). It was plastically deformable, retained its shape upondeformation, and was not pourable at the ambient temperature of about23±2° C. When heated to about 37° C. the suspension became pourable, butjust barely.

Centrifugation of 4.5 mL of the suspension for 1 hour in a 15 mL, 110 mmlong centrifuge tube at 5000 rpm did not cause observable sedimentationof LD, nor did it cause separation of an aqueous phase from an oilphase, or any other visible change in the appearance of the suspension,which remained homogeneous. The relative centrifugal force was about3000 G, i.e., about 3,000 times that of gravitational acceleration.

To test if the suspension was a water-in-oil emulsion or an oil-in-wateremulsion some of the suspension was added to two test tubes, onecontaining canola oil and the other containing water. The suspension didnot disperse in canola oil, but it dispersed promptly in water, showingthat it was an oil-in-water dispersion, i.e., that its continuous phasewas aqueous even though it contained much less water than oil.

About 19 mL of the suspension was transferred to a 20 mL Crn® CRONO®syringe. The estimated density was 1.12 g/mL, calculated by assumingthat the density of LD is about 1.5 g/mL. The suspension was deliveredwith the Crono Par at a flow rate of 1 mL/hour via a 28 cm long 2.4 mminternal diameter tubing coupled through the luer lock of the syringe.The entire volume in the syringe was delivered, i.e., the pump did notocclude. There was no filtering or solid cake formation and theextrudate appeared to be homogenous and unchanged through the 18 hourlong extrusion period, in which 20.4 g of the suspension were delivered.Assuming that 18 mL were delivered in the 18 hour delivery period, thedensity of the extrudate was 1.13 g/mL, consistent with the calculateddensity of 1.12 g/mL and suggesting that there was little or no trappedair in the suspension, i.e., that the trapped air was removed by thecentrifugation.

Example 10. Showing Continuous Extrusion with No Significant Change inDensity of a 523 mg/mL (2.7 M) LD Suspension

Ingredients: LD (>95 weight % of the particles passing 250 μm sieveopenings and about 30 weight % passing 125 μm sieve openings); canolaoil (from Safeway); Polysorbate 60 (from Sigma); De-ionized water.

Most of the LD was particulate, i.e. it was not dissolved.

1.43 g of Polysorbate 60 was dissolved with stirring in 14.12 g ofcanola oil. The solution was clear, i.e., it had no suspended lightscattering matter. 13.2 g of the solution, containing 1.2 g ofPolysorbate 60 and 11.1 g of canola oil, were transferred to an about100 mL mortar and 13.03 g LD was added. The mixture was hand-ground tohomogeneity in about 15 min, then 3 g of water was added and the mixturewas re-ground for about 30 min. During the grinding themixture-containing mortar was periodically weighed and water was addedas needed to compensate for evaporated water. The LD concentration inthe resulting suspension was about 523 mg/mL (2.7 M). Its density wasabout 1.17 g/mL assuming that the density of LD is about 1.5 g/mL. Thesuspension was non-pourable at the ambient temperature of about 23±2° C.It was soft, compliant, easy to mechanically deform, mayonnaise-like butharder, and easy to squeeze through a nozzle. When force was applied itextruded through a nozzle as a plug.

Most of the suspension was transferred to a 20 mL Crn® CRONO® syringe.To remove trapped large air bubbles the filled syringe was warmed toabout 40° C. and while it was held with its outlet pointing upward thebubbles rose, coalesced near the outlet, and were expelled. The weightof the suspension filling the syringe to its 20 mL graduation mark was22.37 g, i.e., its density was about 1.12 g/mL, less than the calculateddensity of 1.17 g/mL, suggesting a trapped air residue.

The syringe was inserted in a Cane CronoPAR pump and a 28 cm long 2.4 mminternal diameter plastic tubing was coupled to its luer lock. The pumpwas set to deliver 1 mL/hr for 20 hours. The extrudate was weighed after5, 8, 13 and 20 hours of extrusion. The weight gain corresponded to thatexpected for the delivery of a 1.11 g/mL density suspension at 1 mL/hourrate through the first 13 hours, then for the delivery of a 1.08 g/mLsuspension in the last 7 hour period. The lesser gain than expected for1.12 g/mL density are attributed to water evaporation from the extrudatecollecting vial, that was open to air. It was not caused by an actualconcentration change, as there was no caked, concentrated or hardLD-rich residue left in the syringe when the 20 mL extrusion wascompleted and the syringe was empty.

The example shows that it is feasible to extrude a suspension containingabout 523 mg/mL (2.7 M) LD and to maintain for a 13 hour period a nearlyconstant extrudate density, the extrudate comprising an edible oil,water and an also edible surfactant. It also shows that in 20 hours ofextrusion the density can be constant within about ±1.4% or less.

Example 11. Showing that a Suspension Containing 625 mg/mL (3.17 M) LDand 156 mg/mL (0.74 M) CD is Physically Stable when Centrifuged for 1Hour at 16,000 G and that it Also Physically Stable at 60° C. for 24Hours

Ingredients: LD (D₅₀ about 75 μm, D₉₀ about 200 μm). CD (D₉₅ about 100μm, D₈₀ about 45 μm); Polysorbate 60 (Sigma Aldrich Catalog #95754-F);Miglyol 812 (Peter Cremer, Cincinnati, Ohio); butylated hydroxyanisole(BHA) antioxidant FCC (Spectrum, XV3021); de-ionized water.

Most of the LD and most of the CD were particulate, i.e., they were notdissolved. The composition comprised 50.0 weight % (w/w) LD; 12.5 weight% CD; 24.4 weight % Miglyol 812; 5 weight % of Polysorbate 60; and 8.0weight % water. It was prepared as follows: (a) The LD (5 g) and CD(1.25 g) powders were mixed for 15 min to homogeneity; (b) ThePolysorbate 60 (0.5 g) was mixed with deionized water (0.8 g), themixture was warmed to about 60° C. and homogenized by thorough mixing;(c) the LD and CD powder mixture of (a) and 10 mg of BHA were added tothe Polysorbate 60 and water of (b) and mixed thoroughly. The mixturewas kept at ambient temperature for 4 hours; (d) after the 4 hours, 2.44g of Miglyol 812 containing 10 mg of BHA was added, mixed thoroughly,then the mixture was aged at ambient temperature for at least 2 hours.

There was no visible sedimentation of the solid drug particles nor wasthere any visible phase separation of the oil and the water upon 1 hourcentrifugation at about 16,000 G (G being the gravity at about sealevel), suggestive of shelf life physical stability for about 22 monthsat 1 G and room temperature. The suspension also remained unchanged,i.e., homogeneous, after storage for 24 hours at about 25° C., 40° C.,and 60° C.

Example 12. Describing a Deformable Plug Material for Separating thePropellant from the Suspension

For a mobile plug that could replace the piston in a device where theformulation is delivered into the mouth by the about constant pressureof a propellant, a paste was made of 2 g graphite (Timrex SFG44, Timcal,Westlake, Ohio, average particle (flake) size 44 microns) mixed with 6 gof Fomblin Y (Sigma). The plug may be impermeable to the propellant andalso to the drug containing formulation.

Example 13. Showing that in the Absence of Solid Drug Particles theCarrier Emulsions can be Physical Unstable and that the Suspension arePhysically Stabilized by Adding Solid Drug Particles

-   -   (a) First phase separating, unstable emulsion in the absence of        solid drug particles.        -   An emulsion was made by dissolving with warming 0.8 g            Kolliphor RH 60 in 1.5 g water, then adding 4.6 g canola oil            and shaking. Part of the emulsion visibly phase separated            after 1 hour at room temperature even without            centrifugation.    -   (b) Second phase separating, unstable emulsion in the absence of        solid drug particles.        -   An emulsion was made by dissolving 0.8 g Polysorbate 60 in            4.6 g canola oil, then adding 1.5 g water and shaking. The            emulsion was intensely light scattering, milky and viscous.            It did not visibly phase separate at room temperature for at            least 12 hours, but when centrifuged in a 10 cm long test            tube at 10,000 rpm for 10 min it phase separated, i.e., it            was physically unstable.    -   (c) To test if dissolved (not solid) LD and CD stabilized the        second emulsion, the water was replaced with an aqueous solution        saturated in LD and CD. The emulsion was intensely light        scattering, milky and viscous. It did not visibly phase separate        at room temperature for at least 12 hours, but when centrifuged        in a 10 cm long test tube at 10,000 rpm for 10 min phase        separation was observed. Saturation of the phases of the        emulsion with LD and with CD did not prevent phase separation        upon 10 min centrifugation.    -   (d) As shown in Example 11 the suspension made with the        emulsions of (b) or (c) but containing 625 mg/mL (3.17 M) LD and        156 mg/mL (0.74 M) CD is stable when centrifuged for 1 hour at        16,000 G and is also stable at 60° C. for 24 hours.

Example 14. Presence and Absence of LD and CD Decomposition Products,Including Toxic Hydrazine in Various Formulations after 0, 1, and 2Weeks of Aging

Chemicals:

-   -   Micronized LD with the following particle size distribution:

D₁₀ 0.9 μm D₅₀ 7.1 μm D₉₀ 15.9 μm 

-   -   Micronized CD with the following particle size distribution:

D₁₀ 1 μm D₅₀ 4 μm D₉₀ 13 μm 

-   -   Phosphoric acid (85%), HPLC grade    -   Citric acid monohydrate, USP    -   Glacial acetic acid, USP    -   Sodium hydroxide, NF    -   EDTA, USP    -   Light mineral oil, NF    -   Vitamin E, USP    -   Glycerin, USP    -   Super refined PEG 600        Buffers of 50 mM concentration shown in Table 6 were prepared.        The weights in mg shown in Table 6 are for 50 mL of the buffer        solutions.

TABLE 6 Buffer preparation parameters. mg/50 mL F-1 F-2 F-3 F-4 F-5 F-6F-7 F-8 F-9 Phosphoric acid (85%) 290 290 290 290 290 Glacial aceticacid 150 150 Citric acid 525 EDTA 75 DI-water QS QS QS QS QS QS QS QS pHby NaOH As is 2 2.5 3 4 5 6 7 2.5

The buffers were compounded according to Table 7 with micronized LD andmicronized CD. The weights of added LD and CD in mg per 1 g ofcompounded suspension are shown in Table 7. In Table 7, QS means“quantity sufficient to make a total of 1 g suspension”. In Table 8, QSmeans “quantity sufficient to make a total of 1.25 g suspension”.

TABLE 7 Suspension preparation parameters. mg/g F-1 F-2 F-3 F-4 F-5 F-6F-7 F-8 F-9 Micronized LD 600 600 600 600 600 600 600 600 600 MicronizedCD 150 150 150 150 150 150 150 150 150 Phosphate buffer QS QS QS QSAcetate buffer QS QS Citrate buffer QS Phosphate buffer with EDTA QSDI-water QS

TABLE 8 Suspension preparation parameters. mg/1.25 g F-10 F-11 F-12 F-13F-14 Micronized LD 600 600 600 600 600 Micronized CD 150 150 150 150 150Miglyol 812 QS Light mineral oil QS Vitamin E QS Glycerin QS PEG 600 QS

For the assessment of the stabilities the following protocol wasfollowed to prepare buffers and suspensions: 290 mg of 85% phosphoricacid was added to a 50-mL Falcon tube; it was diluted with de-ionizedwater to about 80% of the volume of the tube; the pH was adjusted to2.0, 2.5, 3.0 or 7.0 with 5N NaOH; the solution was diluted to theintended 50 mL volume with de-ionized water. Alternatively 75 mg EDTAwas dissolved and its pH was adjusted to 2.5 or 5.0 by 5N NaOH; 150 mgglacial acetic acid was added to a 50-mL Falcon tube, diluted with DIwater to 80% of the volume of the tube, the pH was adjusted to 4.0 by 5NNaOH; the solution was diluted with DI water to the intended 50 mLvolume. Alternatively 480 mg citric acid was added to a 50 mL Falcontube and dissolved in about 40 mL DI water, the pH was adjusted to 6.0by 5N NaOH and the solution was diluted with DI water to the intended 50mL volume.

For making the suspensions, 9.00 g micronized LD and 2.25 g micronizedCD was added to a 50 mL Falcon tube, tumble mixed for 15 min to create auniform mixture of the two drugs, then 750 mg of the LD-CD mixture addedto each of a group of 1.5 mL Eppendorf tubes and enough of the vehiclewas added for the weight to total 1.25 g in each tube. After mixing witha BeadBeater (BB) for 2×2 min, the pH was recorded the tubes wereincubated at 60° C. for physical and chemical stability tests bywithdrawing samples after 0, 1 and 2 weeks. For each withdrawn samplethe appearance and pH were recorded, then the content was diluted to 0.5mg/mL and the vial containing the sample was weighed. The content ofeach vial was then HPLC analyzed. The HPLC peaks of the drugs and of theimpurities were recorded. The areas of all impurities combined as theirpercentage of the drugs are summarized in Table 9, showing the % peakimpurity area of the total drug peak area.

TABLE 9 Impurities drug formulations. ID 0 day, % 1 week, % 2 week, % F1<0.05 <0.05 F2 <0.05 <0.05 F3 <0.05 <0.05 <0.05 F4 <0.05 0.07 ND F5<0.05 0.06 ND F6 <0.05 0.05 ND F7 <0.05 0.07 ND F8 <0.05 0.05 ND F9<0.05 <0.05 ND F10 <0.05 <0.05 ND (<1.1% USP spec) F11 <0.05 <0.05<0.05% (<1.1% USP spec) F12 <0.05 <0.05 0.2 F13 <0.05 0.16 ND F14 <0.050.07 ND

A known toxic impurity is hydrazine, whose buildup requires frozenstorage of Duodopa™ and limits its labeled refrigerated shelf life to 12weeks after thawing. Hydrazine concentrations, in micrograms per mg ofthe combined weights of LD and CD, in the various aged formulations areseen in Table 10. ND means not detected.

TABLE 10 Hydrazine concentrations in drug formulations. After oneInitial week at (μg/mg of 60° C. (μg/mg of After 2 weeks at 60° C.Sample ID LD + CD) LD + CD) (μg/mg of LD + CD) F1 0.47 0.54 ND F2 0.450.89 ND F3 0.49 0.45 0.74 F4 0.56 1.02 ND F5 0.49 0.90 ND F6 0.54 0.75ND F7 0.49 1.33 ND F8 0.65 1.43 ND F9 0.47 0.87 ND F10 0.78 0.58 0.15(<1.6 in-house spec) F11 0.51 0.74 0.19 (<1.6 in-house spec) F12 0.500.69 0.26 F13 0.47 1.20 ND F14 0.45 1.00 ND

Overall, impurities contributed less than <0.1% to the total peak areas,suggesting good chemical stability. Formulations F13, containingglycerin, and F14 containing PEG600, contained after their aging moreimpurities than the other formulations, i.e., were chemically lessstable. Hydrazine levels were below the target level of 1.6 μg/mg of theweight of the combined LD and CD, which is below the hydrazine exposurelimit for Duodopa™.

Example 15. Showing the Chemical Stability of Formulations ComprisingSolid LD and CD Dispersed in Oils with Various Surfactants, and thatAddition of Water is Associated with an Increase in Hydrazine Formationand with Discoloration Indicative of Air Oxidation

Ingredients: The LD, CD, Miglyol 812, Kolliphor RH 40 (also known asCremophor RH 40) and water were those of Example 11. Other ingredientswere Polysorbate 60, NF; vitamin E, TPGS; Span 60; hydrogenated soylecithin (LIPOID SPC3); Poloxamer 188; glyceryl monosterate; polyvinylalcohol (PVA), stearic acid, propylene glycol, and canola oil.

Formulations prepared and tested are summarized in Table 11 and Table12. The values in the boxes of Table 11 are weight percentages ofconstituents of the formulations and are weights in mg per 1.2 g offormulation in Table 12. QS means in Table 12 “quantity sufficient tomake 1.2 g when added to the other ingredients.”

TABLE 11 Formulations prepared and tested. Weight % F15 F16 F17 F18 F19F20 F21 F22 F23 F24 F10 F25 F26 F27 LD 50.3 50.3 50.3 50.3 50.3 50.350.3 50.3 50.3 50.3 50.3 50.3 50.3 50.3 CD 12.6 12.6 12.6 12.6 12.6 12.612.6 12.6 12.6 12.6 12.6 12.6 12.6 12.6 Miglyol 812 32.1 24.3 32.1 32.132.1 32.1 32.1 32.1 32.1 32.1 37.1 24.3 Polysorbate 60 5 5 5 5 5 VitaminE TPGS 5 Span 60 5 Cremophor 5 (Kolliphor) RH40 Lecithin SPC3 5Poloxamer 188 5 Glyceryl 5 monostearate PVA 5 Stearic acid 5 H₂O (DIwater) 7.9 7.9 Canola oil 24.3 24.3 BHA 0.1 Propylene glycol 7.9 7.9

TABLE 12 Formulations prepared and tested. mg/1.2 g F15 F16 F17 F18 F19F20 F21 F22 F23 F24 F10 F25 F26 F27 LD 600 600 600 600 600 600 600 600600 600 600 600 600 600 CD 150 150 150 150 150 150 150 150 150 150 150150 150 150 Polysorbate 60 60 60 60 60 60 Vitamin E TPGS 60 Span 60 60Cremophor 60 (Kolliphor) RH40 Lecithin SPC3 60 Poloxamer 188 60 Glyceryl60 monosterate PVA 60 Steric acid 60 Water 94 94 Miglyol 812 QS QS QS QSQS QS QS QS QS QS QS — QS — Canola oil + BHA 290 290 BHA 1.2 1.2Propylene 94 94 glycol

The formulations were prepared as follows: LD and CD at a 4:1weight/weight ratio was weighed into a 50 mL Falcon tube, then mixed touniformity by tumble mixing for 15 min. 750 mg of the 4:1(weight/weight) mixture of LD and CD was transferred to a 1.5 mLEppendorf vial and the weight was recorded. In a second tube 600 mg ofsurfactant was mixed to uniformity with 3900 mg of Miglyol 812. 450 mgof the surfactant-Miglyol mixture was added to the Eppendorf tubecontaining the 760 mg LD and CD and the weight was recorded, mixed touniformity, warmed to 60° C. to complete the mixing, then the two mixingsteps were repeated. Each mixing was in a BeadBeater (BB), was of 2 minduration and was repeated.

In formulation F16, 600 mg surfactant, 940 mg DI water and 2960 mgMiglyol 812 were mixed to uniformity in an empty Eppendorf tube, warmedto 60° C. to complete the mixing, using for the mixing a BeadBeater(BB), twice for 2 min.

The formulations were transferred to a new Eppendorf vials and referencevials were stored at 2-8° C., while the test-vials were stored at 60° C.After one week of storage at 60° C. the test samples were checked forcolor change indicating oxidation and assayed by HPLC for impurities,their impurity concentrations compared with those of the referencesamples stored at 2-8° C. The results are summarized in Table 13.

Upon 1 week storage at 60° C. the hydrazine concentrations increasedmeasurably in the water-containing formulations F16 and F25. Theseformulations as well as the propylene glycol comprising formulations,also changed their color, showing that water and propylene glycolenhanced the rate of air-oxidation to colored products relative to therate in oils, suggesting that mostly or only dissolved LD and/or CD wasair oxidized. In most of the formulations made with the 2 oils and 7surfactants the impurity levels remained very low. The results alsoidentify several surfactants potentially suitable for use in suspensionsof the inventions.

TABLE 13 Impurities in drug formulations. Impurities Impurities (% ofthe sum of all peak areas) (% of the sum of all peak areas) ID at startafter 1 week storage at 60° C. F15 <0.05 <0.05 F16 <0.05 <0.05 F17 <0.05<0.05 F18 <0.05 0.07 F19 <0.05 0.06 F20 <0.05 0.05 F21 <0.05 0.07 F22<0.05 0.05 F23 <0.05 <0.05% F24 <0.05 <0.05% F25 <0.05 <0.05% F26 <0.05<0.05% F27 <0.05 0.09

Example 16. Showing the Discovery of Novel, Physically and ChemicallyStable, Extrudable Suspensions Containing 62.5 Weight % of Drug

Ingredients: The LD, CD, Miglyol 812, and water were those of Example11; other ingredients were Polysorbate 60, NF (Spectrum, 1CK0247),canola oil (Spectrum, 1DK0517), and BHA antioxidant (Spectrum, XV3021).

The formulations, in mg per 1.5 g of prepared suspension, are listed inTable 14. The oil (Miglyol 812 or canola oil) to polysorbateweight/weight ratio was constant at 6.5:1.

TABLE 14 Suspensions prepared. mg/1.5 g F29 F30 F16 F31 F32 F33 F34 F35F36 LD 750 750 750 750 750 750 750 750 750 CD 187.5 187.5 187.5 187.5187.5 187.5 187.5 187.5 187.5 Miglyol 812 + Polysorbate 60 500 470 440410 380 350 440 350 (6.5:1, w/w) Canola oil + Polysorbate 60 440 (6.5:1,w/w) BHA 1.5 1.5 1.5 1.5 1.5 1.5 1.5 1.5 1.5 DI-H₂O 60 90 120 150 180210 0 210 120 (4%) (6%) (8%) (10%) (12%) (14%) (14%) (8%) 50 mM PBS (pH2.7) 120 (8%)

The suspensions were prepared as follows:

A 50 mM, pH 2.7 sodium phosphate buffer solution was prepared.

To each of a series of 1.5 mL Eppendorf vials, 750 mg of a mixture of LDand CD was added, the added mixture comprising 600 mg of LD and 150 mgCD, followed by the Miglyol 812 or canola oil containing the Polysorbate60 of which the amounts shown in Table 14 were added. Next either DIwater or 50 mM, pH 2.7 phosphate buffer was added in the amounts shownin Table 14, then the components were mixed using a BeadBeater (2×2min). For formulation F35, but not for the other formulations, water wasvacuum evaporated, leaving 40 mg of the initial 210 mg of the water.

Next, the 1.5 g of the formulation in each Eppendorf vial was split,i.e., 750 mg was transferred to a second Eppendorf vial. One vial ofeach formulation was closed and stored at 60° C. and the second wascentrifuged at 13,000 rpm, providing an acceleration of 16,060 G (16,060times that of sea level gravity) for 1 hour at 25° C.

After checking for phase separation, 15 mg samples were drawn from thetop layer and from the bottom layer of each of the centrifugedsuspensions and transferred into 15 mL 0.01 N phosphoric acid diluentcontaining Falcon tubes for HPLC assays, so as to determine if the topand bottom layers of the 16,060 G centrifuged suspensions differed intheir LD or CD concentrations.

The same centrifugation test and assay were then performed on each ofthe suspensions after storage for 1 week at 60° C.

Occlusion was observed upon attempted manual extrusion of suspension F35from a filled 1.0 mL syringe with a 16 gauge, 26 mm long nozzle. None ofthe other suspensions occluded in identical tests, i.e., in each caseall of the 1 mL in the syringe passed through the nozzle.

Suspensions F16 (containing 8 weight % water), F29 (containing 4 weight% water), F30 (containing 6 weight % water), and F36 (containing 8weight % water) did not show phase separation upon centrifugation. Ofthese, F16, F29 and F30 were made with Miglyol 812, while F36 was madewith canola oil. Suspension F34 is similar to F16, except for its pH of2.7.

Assays of samples taken from the top and from the bottom layers ofcentrifuged suspensions F16, F34 and F36 after their storage for 1 weekat 60° C. are provided in Table 15.

The estimated densities and drug concentrations in the suspensions thatdid not sediment or phase separate upon centrifugation for 1 hour at16,060 G are as follows:

-   -   Suspension F16 with an estimated density of about 1.24 g/mL at        about 25° C. contains about 621 mg/mL of LD and about 155 mg/mL        CD, i.e., the respective molar concentrations of LD and CD are        3.15 M and 0.73 M.    -   Suspension F29 with an estimated density of about 1.24 g/mL at        about 25° C. contains about 619 mg/mL of LD and about 155 mg/mL        CD, i.e., the respective molar concentrations of LD and CD are        3.14 M and 0.73 M.    -   Suspension F30 with an estimated density of about 1.24 g/mL at        about 25° C. contains about 620 mg/mL of LD and about 155 mg/mL        CD, i.e., the respective molar concentrations of LD and CD are        3.15 M and 0.73 M.    -   Suspension F36 with an estimated density of about 1.23 g/mL at        about 25° C. contains about 613 mg/mL of LD and about 153 mg/mL        CD, i.e., the respective molar concentrations of LD and CD are        3.11 M and 0.72 M.    -   Suspension F34 is similar to F16, except for its pH of 2.7.

Of the suspensions that were stored for one week at 60° C., formulationsF16, F34 and F36 did not show visible phase separation aftercentrifugation at 16,060 G for 1 hour. Importantly, after centrifugationthe top and bottom layer LD and CD concentrations of F16 and of F36 werenot significantly different, making these the preferred compositions ofthe series. Their water content was about 8 weight %, their oil contentwas about 25 weight %, their surfactant content was about 4 weight %,and they contained about 62.5% by weight of the drugs. The suspensionsalso contained 0.1 weight % of the antioxidant.

TABLE 15 Top and Bottom Layer LD and CD Concentrations After 1 WeekStorage at 60° C. and 1 Hour Centrifugation at 16,060 G. LD Sample(mg/g) CD (mg/g) F16-Top 0.52 0.13 F16-Bottom 0.53 0.14 F34-Top 0.390.10 F34-Bottom 0.51 0.13 F36-Top 0.50 0.13 F36-Bottom 0.51 0.13

Example 17. Showing Physically and Chemically Stable Suspensions forManaging Parkinson's Disease by Continuous Oral Extrusion of LD and CD,Including their Low Rate of Hydrazine Production

Ingredients: The ingredients were those of Example 11 or 15; theCremophor (Kolliphor) RH40 USP/NF/EP was from BASF.

TABLE 16 Compositions by Weight %. F16 % (w/w) F36 % (w/w) F37 % (w/w)LD 50.0 50.0 50.0 CD 12.5 12.5 12.5 Polysorbate 60 5 5 Cremophor(Kolliphor) RH40 4.2 Miglyol 812 24.4 Canola oil 24.4 24.4 BHA 0.1 0.10.1 DI-H₂O 8.0 8.0 8.0

TABLE 17 Compositions by weight in mg per 1.5 g of product. (mg/1.5 g)F16 F36 F37 LD 750 750 750 CD 187.5 187.5 187.5 DI-H₂O 120 120 120Polysorbate 60 75 75 — Cremophor (Kolliphor) RH40 — — 63 Miglyol 812 366— — Canola oil — 366 378 BHA 1.5 1.5 1.5

For the preparations, 15.0 g LD and 3.75 g CD were mixed for 15 min touniformity in a 50 mL Falcon tube. 75 mg polysorbate 60 or 63 mgCremophor (Kolliphor) RH40 were mixed in an Eppendorf tube with 120 mgDI-H2O, warmed to about 60° C., and mixed by vortexing; the 937.5 mgLD+CD mixture in the Falcon tube was added and the mixture was homenizedwith a BeadBeater twice for 2 min, then allowed stand at about 25° C.for 4 hours after which the Miglyol 812 or canola oil was added. Next1.5 mg of BHA was added and the mixture was homogenized twice each timefor 2 min using a BeadBeater. The suspensions were then divided into 3parts, each of 0.5 g. One was kept at 25° C., the second at 40° C., andthe third at 60° C. for 2 hours. All were centrifuged at 13,000 rpm(producing an acceleration of 16,060 G) for 1 hr at 25° C., and checkedfor phase separation and sedimentation. Next 15 mg of the top and 15 mgof the bottom of the centrifuged suspensions was transferred into 15 mLFalcon tubes for HPLC assays as described in the previous Example.

There was no visually observable phase separation in the centrifugedsuspension F16 made with Miglyol 812 and Polysorbate 60 after aging atany of the three temperatures 25° C., 40° C., or 60° C. Phase separationwas, however, observed in all of the centrifuged F37 suspensions madewith Miglyol 812 and Cremophor (Kolliphor) RH 40. The F36 suspensionmade with canola oil and Polysorbate 60 did not phase separate upon itscentrifugation after 24 hour aging at 60° C., but it did phase separateafter its aging for 24 hours at the two lower temperatures, 25° C. and40° C., showing that aging for 24 hours at 60° C. stabilizes suspensionF36, but aging at 25° C. or 40° C. does not.

TABLE 18 Absence of Substantial Difference in the LD and CDConcentrations of Top and Bottom Layers of Centrifuged, Differently AgedF16 Suspensions (containing 50 weight % LD and 12.5 weight % CD). 24Hour Aging Temp, ° C. LD (mg/g) CD (mg/g) Fresh LD & CD 2 to 8 0.54 0.14Centrifuged, top 25 0.50 0.13 Centrifuged, bottom 25 0.49 0.13Centrifuged, top 40 0.52 0.13 Centrifuged, bottom 40 0.50 0.13Centrifuged, top 60 0.53 0.13 Centrifuged, bottom 60 0.51 0.13

TABLE 19 Hydrazine Concentrations in Aged F16 Suspensions. 24 Hour AgingHydrazine/(LD + CD), Temperature, ° C. μg/mg* Fresh LD & CD (baseline) 2to 8 0.61 Centrifuged, top 25 0.62 Centrifuged, bottom 25 0.59Centrifuged, top 40 0.81 Centrifuged, bottom 40 0.84 Centrifuged, top 600.85 Centrifuged, bottom 60 0.91 *The target hydrazine concentration is1.6 μg per mg of combined LD and CD.

The F16 formulation has no taste, which is a desirable feature.

Example 18. Showing that a Suspension Containing 625 mg/mL (3.17 M) LD,156 mg/mL (0.74 M) CD, and Poloxamer 188 Surfactant is Physically Stablewhen Centrifuged for 1 Hour at about 16,000 G, is Chemically Stable at60° C. for 24 Hours, that its Rate of Hydrazine Formation is Slow, andthat it is Tasteless

Ingredients: LD (D₅₀ about 75 μm, D₉₀ about 200 μm). CD (D₉₅ about 100μm, D₈₀ about 45 μm); Poloxamer 188 (NF BAS WPDX-577B); Miglyol 812(Peter Cremer, Cincinnati, Ohio); butylated hydroxyanisole (BHA)antioxidant FCC (Spectrum, XV3021); de-ionized water.

Most of the LD and most of the CD in the suspension were particulate,i.e., they were not dissolved. The suspension comprised 50.0 weight %(w/w) LD; 12.5 weight % CD; 24.4 weight % Miglyol 812; 5 weight % ofPoloxamer 188; and 8.0 weight % water. It was prepared as follows: (a)the LD (5 g) and CD (1.25 g) powders were mixed for 15 min tohomogeneity; (b) the Poloxamer 188 (0.5 g) was mixed with deionizedwater (0.8 g), the mixture was warmed to about 60° C. and homogenized bythorough mixing; (c) the LD and CD powder mixture of (a) and 10 mg ofBHA were added to the Poloxamer 188 and water of (b) and mixedthoroughly. The mixture was kept at ambient temperature for 4 hours; (d)after the 4 hours, 2.44 g of Miglyol 812 containing 10 mg of BHA wasadded, mixed thoroughly, then the mixture was aged at ambienttemperature for at least 2 hours then centrifuged. There was no visiblesedimentation of the solid drug particles nor was there any visiblephase separation of the oil and the water upon 1 hour centrifugation at13,000 rpm providing an acceleration of about 16,000 G (G being thegravity at about sea level), suggestive of shelf life physical stabilityfor about 22 months at 1 G and room temperature. The suspension alsoremained unchanged, i.e., homogeneous, after storage for 24 hours atabout 25° C., 40° C., and 60° C.

After centrifugation of the suspension that was stored for 2 hours ormore at about 25° C., the top and bottom layers were assayed for LD, CDand hydrazine. The difference in their LD and CD content was less thanabout 2% and was within the resolution limit of the assay. The hydrazineconcentration was only slightly higher than in the 0.52 μg/mg of thecombined weights of LD and CD in the freshly made suspension. Thehydrazine concentrations increased in the top and bottom layersrespectively only to 0.56 μg/mg and 0.61 μg/mg, well below the targetedupper limit of 1.6 μg/mg. The composition was tasteless.

Example 19. Showing that a Suspension Containing 625 mg/mL (3.17 M) LD,156 mg/mL (0.74 M) CD, and Cremophor RH40 Surfactant is PhysicallyStable when Centrifuged for 1 Hour at about 16,000 G, Physically Stableat 60° C. for 24 Hours, Chemically Stable at 60° C. for a Week, and thatthe Rate of Hydrazine Formation is Slow Even at 60° C. in theAir-Exposed Suspension

Ingredients: LD (D₅₀ about 75 μm, D₉₀ about 200 μm). CD (D₉₅ about 100μm, D₈₀ about 45 μm); Cremophor RH40 (USP/NF/EP; BASF; 78105416K0);Miglyol 812 (Peter Cremer, Cincinnati, Ohio); butylated hydroxyanisole(BHA) antioxidant FCC (Spectrum, XV3021); de-ionized water.

Most of the LD and most of the CD in the suspension were particulate,i.e., they were not dissolved. The composition comprised 50.0 weight %(w/w) LD; 12.5 weight % CD; 24.4 weight % Miglyol 812; 5 weight % ofCremophor RH40; and 8.0 weight % water. It was prepared as follows: (a)the LD (5 g) and CD (1.25 g) powders were mixed for 15 min tohomogeneity; (b) the Cremophor RH40 (0.5 g) was mixed with deionizedwater (0.8 g), the mixture was warmed to about 60° C. and homogenized bythorough mixing; (c) the LD and CD powder mixture of (a) and 10 mg ofBHA were added to the Cremophor RH40 and water of (b) and mixedthoroughly. The mixture was kept at ambient temperature for 4 hours; (d)after the 4 hours, 2.44 g of Miglyol 812 containing 10 mg of BHA wasadded, mixed thoroughly, then the mixture was aged at ambienttemperature for at least 2 hours and centrifuged at 13,000 rpm providingan acceleration of about 16,000 G. There was no visible indication ofsedimentation of the solid drug particles nor was there any visibleindication of phase separation of the oil and the water upon 1 hourcentrifugation at about 16,000 G (G being the gravity at about sealevel), suggestive of shelf life physical stability for about 22 monthsat 1 G and room temperature. The suspension also remained unchanged,i.e., homogeneous, after storage for 24 hours at about 25° C., 40° C.,and 60° C. After the centrifugation of the composition that was storedfor 2 hours at about 25° C. the top and bottom layers were assayed forLD, CD and hydrazine. The difference in their LD and CD content was lessthan about 2%, within the resolution limit of the assay. The hydrazineconcentrations were only slightly higher than the initial 0.52 μg/mg ofthe combined weights of LD and CD: the respective hydrazineconcentrations in the top and bottom layers of the centrifugedcomposition were only 0.67 μg/mg and 0.60 μg/mg of the combined weightsof LD and CD, well below the targeted upper limit of 1.6 μg/mg. After aweek of storage at 60° C. the hydrazine concentration was still only0.76 μg/mg of the combined weights of LD and CD. Furthermore, theconcentration of all other impurities as measured by their percentage ofthe HPLC peaks was less than 0.05% after 1 week of storage at 60° C. Theformulation has an acceptable, slightly bitter taste.

Example 20. An 80 mg/mL Baclofen-Comprising Orally Extrudable Paste forManaging Spastic Conditions in Multiple Sclerosis and Cerebral Palsy

0.8 g Poloxamer 188 can be mixed to homogeneity with 1.5 g water bywarming to 60° C. 1.32 g of Baclofen and 12 g of L-tyrosine can be addedand the mixture can be homogenized, then allowed to age for 10 hourswith periodic mixing. Next 4.75 g of the medium chain triglycerideMiglyol 812 can be the Baclofen-L-tyrosine-Poloxamer 188-water paste,homogenized and allowed to age for 3 hours with periodic mixing. Theresulting paste can be physically stable upon centrifugation at 3000 Gand it can be centrifuged to remove trapped air. Its expected density at23±2° C. is 1.25 g/mL±0.05 g/mL. The paste is expected to be soft,compliant, and easy to mechanically deform and to retain at 23±2° C. itsshape after deformation. The paste is not expected to be pourable at23±2° C., but at 37±2° C. it could be extruded. At a continuousextrusion rate of 0.04 mL/hour, 0.64 mL of the paste, containing about51.2 mg of Baclofen, would be extruded over 16 awake hours into themouth.

Example 21. An 80 mg/mL Baclofen-Comprising Orally Pumpable Suspensionfor Managing Spastic Conditions in Multiple Sclerosis and Cerebral Palsy

Cocoa butter, an edible oil extracted from cocoa beans, has a typicalmelting range of about 34° C.-36.5° C., so that it is a solid at roomtemperature but becomes liquid at body temperature. An 80 mg/mLsuspension of Baclofen can be prepared by homogenizing 1.9 g Baclofenwith 20 g of cocoa butter. The volume of the suspension at 37±2° C. isexpected to be about 23.7 mL and the Baclofen concentration is expectedto be at 37±2° C. near 80 mg/mL. At 0.04 mL/hour flow rate about 0.64 mLof the solution containing about 0.51 mg of Baclofen could be pumpedinto the mouth in 16 awake hours.

Example 22. A 50 mg/mL Treprostinil-Comprising Orally Extrudable Pastefor Pulmonary Arterial Hypertension Management

Ingredients: Treprostinil (Bio-Techne Minneapolis, Minn.); L-tyrosine,nominal particle size 20 μm; Poloxamer 188; Miglyol 812 (Peter Cremer,Cincinnati, Ohio); de-ionized water.

0.8 g Poloxamer 188 can be mixed to homogeneity with 1.5 g water bywarming to 60° C. 12 g of L-tyrosine can be added and the mixture can behomogenized, then allowed to age for 10 hours with periodic mixing. 0.8g of treprostinil can be dissolved in 4.75 g of the medium chaintriglyceride Miglyol 812. The treprostinil solution in Miglyol 812 canbe mixed with the L-tyrosine-Poloxamer 188-water paste, homogenized andallowed to age for 3 hours with periodic mixing. The resulting paste canbe physically stable upon centrifugation at 3000 G and it can becentrifuged to remove trapped air. Its expected density at 23±2° C. is1.25 g/mL±0.05 g/mL. The paste is expected to be soft, compliant, andeasy to mechanically deform and to retain at 23±2° C. its shape afterdeformation. The paste is not expected to be pourable at 23±2° C., butat 37±2° C. it could be extruded. At a continuous extrusion rate of 0.02mL/hour, 0.32 mL of the paste, containing about 16 mg of treprostinil,would be extruded over 16 awake hours into the mouth.

Example 23. An 80 mg/mL Midoridine-Comprising Orally Extrudable Pastefor Managing Spastic Conditions in Multiple Sclerosis and Cerebral Palsy

0.8 g Poloxamer 188 can be mixed to homogeneity with 1.5 g water bywarming to 60° C. 1.32 g of Midoridine and 12 g of L-tyrosine can beadded and the mixture can be homogenized, then allowed to age for 10hours with periodic mixing. Next 4.75 g of the medium chain triglycerideMiglyol 812 can be the Baclofen-L-tyrosine-Poloxamer 188-water paste,homogenized and allowed to age for 3 hours with periodic mixing. Theresulting paste can be physically stable upon centrifugation at 3000 Gand it can be centrifuged to remove trapped air. Its expected density at23±2° C. is 1.25 g/mL±0.05 g/mL. The paste is expected to be soft,compliant, and easy to mechanically deform and to retain at 23±2° C. itsshape after deformation. The paste is not expected to be pourable at23±2° C., but at 37±2° C. it could be extruded. At a continuousextrusion rate of 0.04 mL/hour, 0.64 mL of the paste, containing about51.2 mg of Midoridine, would be extruded over 16 awake hours into themouth.

Example 24. A 0.5 mg/mL Iloprost-Comprising Orally Extrudable Paste forManagement of Pulmonary Arterial Hypertension

Ingredients: 0.5 g Poloxamer 188 can be mixed to homogeneity with 0.8 gdeionized water by warming to about 60° C., and then homogenized with6.25 g of L-tyrosine (D50 about 20 μm particle size) powder by thoroughmixing, aging the mixture at ambient temperature for about 24 hours, andthorough re-mixing. 4 mg of iloprost and 10 mg of BHA (butylatedhydroxyanisole) can be dissolved in 2.44 g of Miglyol 812 and thesolution can be mixed thoroughly with the L-tyrosine-Poloxamer-watermixture, aging the mixture at ambient temperature for at least 24 hours,then thoroughly re-mixing and again aging for about 24 hours. Next themixture can be centrifuged for 1 hour at 16,000 G to remove any trappedair. The resulting mixture can be physically stable, i.e. may not phaseseparate under the centrifugation suggestive of shelf life physicalstability for more than 22 months at normal gravity at 23±2° C. Itsdensity can be 1.25±0.05 g/mL at about 25° C. It can be non-pourable at23±2° C. but can be extruded at 37±2° C. At a continuous extrusion rateof 0.02 mL/hour, 0.36 mL of the paste, containing 0.18 mg of iloprostwould be extruded daily into the mouth over 16 awake hours.

Example 25. A Temperature Sensitive 0.5 mg/mL Iloprost Solution in CocoaButter for Management of Pulmonary Arterial Hypertension

Cocoa butter, an edible oil extracted from cocoa beans, has a typicalmelting range of about 34° C.-36.5° C., so that it is a solid at roomtemperature but becomes liquid at body temperature. A solution ofiloprost can be prepared by melting about 50 g of cocoa butter at about40° C. and then stirring in 28 mg iloprost. The paste can then be putinto the reservoir and upon cooling will solidify. The volume of thecocoa butter at 37±2° C. is expected to be about 56 mL and the iloprostconcentration is expected to be at 37±2° C. 0.5 mg/mL. At 0.02 mL/hourflow rate about 0.32 mL of the solution containing about 0.16 mg ofiloprost could be pumped into the cheek pocket proximally to the buccalmucosa in 16 awake hours.

Example 26. A Temperature Sensitive 50 mg/mL Treprostinil Solution inButter for Management of Pulmonary Arterial Hypertension

An emulsion can be prepared by melting at about 40° C. 10 mL of butter(a water-in-oil emulsion remaining solid when refrigerated, meltingbetween about 32° C. and about 35° C.), then stirring in 500 mg oftreprostinil. The emulsion can then be put into the reservoir and uponcooling will solidify. The reservoir containing the emulsion couldsolidify and stored as a solid in a refrigerator at 8±3° C. At 37±2° C.and at a continuous extrusion rate of 0.02 mL/hour, 0.36 mL of the pasteabout 18 mg of treprostinil would be pumped daily into the cheek pocketnear the buccal mucosa over 16 awake hours.

Example 27. A 1 mg/mL Ciclosenide Solution for COPD or PAH Management

A solution of 1 mg/mL Ciclesonide in glycerol could be prepared bydissolving 100 mg Ciclesonide in 100 mL glycerol. The solution would becontinuously pumped at 10 μL/hour flow rate. Daily 0.24 mL containing0.24 mg of Ciclesonide would be pumped into the mouth near the buccalmucosa.

Example 28. A 1 mg/mL Vilanterol Solution for COPD Management

A solution of 1 mg/mL Vilanterol could be prepared by dissolving 100 mgVilanterol in 100 mL glycerol. The solution would be continuously pumpedat 10 μL/hour flow rate into the mouth. Daily 0.24 mL containing 0.24 mgof Vilanterol would be pumped into the mouth near the buccal mucosa.

Example 29. A 0.2 mg/mL Glycopyrronium Bromide Solution for COPDManagement

A solution of 0.2 mg/mL Glycopyrronium bromide could be prepared bydissolving 20 mg Glycopyrronium bromide in 100 mL water. The solutionwould be continuously pumped at 10 μL/hour flow rate into the mouth.Daily 0.24 mL containing 0.048 mg of Glycopyrronium bromide would bepumped into the mouth near the buccal mucosa.

Example 30. A 1.44 mg/mL Ipratropium Bromide Solution for COPDManagement

A solution of 1.44 mg/mL Ipratropium bromide could be prepared bydissolving 144 mg Ipratropium bromide in 100 mL water. The solutionwould be continuously pumped at 20 μL/hour flow rate into the mouth. In24 hours 0.48 mL containing 0.69 mg Ipratropium bromide would be pumpedinto the mouth near the buccal mucosa.

Example 31. An 833 mg/mL Carbocisteine Paste for COPD Management

Ingredients: Carbocisteine, about 20 μm nominal particle size; Poloxamer188; Miglyol 812 (Peter Cremer, Cincinnati, Ohio); de-ionized water.

0.8 g Poloxamer 188 can be dissolved in 1.5 g water then homogenizedwith 10 g of carbocisteine. The mixture can be allowed to age for 10hours at 23±2° C. with periodic mixing, and then homogenized by thoroughmixing with 4.75 g of the medium chain triglyceride Miglyol 812. Themixture can be allowed to age for at least 12 hours with periodicmixing. The resulting paste can be physically stable upon centrifugationat 3000 G and it can be centrifuged to remove trapped air. The paste isexpected to be soft, compliant, and easy to mechanically deform and toretain at 23±2° C. its shape after deformation. The paste is notexpected to be pourable at 23±2° C., but at 37±2° C. it could beextruded. At a continuous extrusion rate of 0.075 mL/hour, 0.72 mL ofthe paste containing 1.43 g of carbocisteine would be extruded over 24hours into the mouth.

Example 32. A 5 mg/mL Hexoprenaline Sulfate Solution for Reducing theIncidence of Asthma Attacks

A solution of 5 mg/mL Hexoprenaline sulfate could be prepared bydissolving 0.5 g of Hexoprenaline sulfate in 100 mL water. The solutionwould be continuously pumped at 10 μL/hour flow rate into the mouth. In24 hours 0.24 mL containing 1.2 mg Hexoprenaline sulfate would be pumpedinto the mouth near the buccal mucosa.

Example 33. An 800 mg/mL Erythromycin-Comprising Orally Extrudable Pastefor COPD Management

Ingredients: Erythromycin, about 20 μm nominal particle size; Poloxamer188; Miglyol 812 (Peter Cremer, Cincinnati, Ohio); de-ionized water.

0.8 g Poloxamer 188 can be dissolved in 1.5 g water then homogenizedwith 10 g of erythromycin. The mixture can be allowed to age for 10hours at 23±2° C. with periodic mixing, and then homogenized by thoroughmixing with 4.75 g of the medium chain triglyceride Miglyol 812. Themixture can be allowed to age for at least 12 hours with periodicmixing. The resulting paste can be physically stable upon centrifugationat 3000 G and it can be centrifuged to remove trapped air. The paste isexpected to be soft, compliant, and easy to mechanically deform and toretain at 23±2° C. its shape after deformation. The paste is notexpected to be pourable at 23±2° C., but at 37±2° C. it could beextruded. At a continuous extrusion rate of 0.03 mL/hour, 0.72 mL of thepaste containing 576 mg of erythromycin would be extruded over 24 hoursinto the mouth.

Example 34. An 800 mg/mL Erythromycin-Comprising Orally Extrudable Pastefor Management of Gastroparesis, e.g. Diabetic Gastroparesis

Ingredients: Erythromycin, about 20 μm nominal particle size; Poloxamer188; Miglyol 812 (Peter Cremer, Cincinnati, Ohio); de-ionized water.

0.8 g Poloxamer 188 can be dissolved in 1.5 g water then homogenizedwith 10 g of erythromycin. The mixture can be allowed to age for 10hours at 23±2° C. with periodic mixing, and then homogenized by thoroughmixing with 4.75 g of the medium chain triglyceride Miglyol 812. Themixture can be allowed to age for at least 12 hours with periodicmixing. The resulting paste can be physically stable upon centrifugationat 3000 G and it can be centrifuged to remove trapped air. The paste isexpected to be soft, compliant, and easy to mechanically deform and toretain at 23±2° C. its shape after deformation. The paste is notexpected to be pourable at 23±2° C., but at 37±2° C. it could beextruded. At a continuous extrusion rate of 0.01 mL/hour, 0.24 mL of thepaste containing 192 mg of erythromycin would be extruded over 24 hoursinto the mouth.

Example 35. An 30 mg/mL Tizanidine-Comprising Orally Extrudable Pastefor Managing Spastic Conditions in Multiple Sclerosis and Cerebral Palsy

0.8 g Poloxamer 188 can be mixed to homogeneity with 1.5 g water bywarming to 60° C. 0.5 g of Tizanidine and 12 g of L-tyrosine can beadded and the mixture can be homogenized, then allowed to age for 10hours with periodic mixing. Next 4.75 g of the medium chain triglycerideMiglyol 812 can be the Baclofen-L-tyrosine-Poloxamer 188-water paste,homogenized and allowed to age for 3 hours with periodic mixing. Theresulting paste can be physically stable upon centrifugation at 3000 Gand it can be centrifuged to remove trapped air. Its expected density at23±2° C. is 1.25 g/mL±0.05 g/mL. The paste is expected to be soft,compliant, and easy to mechanically deform and to retain at 23±2° C. itsshape after deformation. The paste is not expected to be pourable at23±2° C., but at 37±2° C. it could be extruded. At a continuousextrusion rate of 0.04 mL/hour, 0.64 mL of the paste, containing about20 mg of Tizadinide, would be extruded over 16 awake hours into themouth.

Example 36. An 800 mg/mL Flavoxate-Comprising Orally Extrudable Pastefor Urinary Urge and Incontinence (“Overactive Bladder”) Management

Ingredients: Flavoxate, about 20 μm nominal particle size; Poloxamer188; Miglyol 812 (Peter Cremer, Cincinnati, Ohio); de-ionized water.

0.8 g Poloxamer 188 can be dissolved in 1.5 g water then homogenizedwith 10 g of flavoxate. The mixture can be allowed to age for 10 hoursat 23±2° C. with periodic mixing, and then homogenized by thoroughmixing with 4.75 g of the medium chain triglyceride Miglyol 812. Themixture can be allowed to age for at least 12 hours with periodicmixing. The resulting paste can be physically stable upon centrifugationat 3000 G and it can be centrifuged to remove trapped air. The paste isexpected to be soft, compliant, and easy to mechanically deform and toretain at 23±2° C. its shape after deformation. The paste is notexpected to be pourable at 23±2° C., but at 37±2° C. it could beextruded. At a continuous extrusion rate of 0.04 mL/hour, 0.96 mL of thepaste containing 768 mg of flavoxate would be extruded over 24 hoursinto the mouth.

Example 37. A 1.14 g/mL Magnesium Carbonate Comprising Orally ExtrudablePaste e.g. for Managing a Neurological Disorder Like Alzheimer's Diseaseor Parkinson's Disease

Ingredients: Magnesium carbonate, about 20 μm nominal particle size;Poloxamer 188; Miglyol 812 (Peter Cremer, Cincinnati, Ohio); de-ionizedwater.

0.8 g Poloxamer 188 can be dissolved in 5 g water then homogenized with20 g of magnesium carbonate. The mixture can be allowed to age for 10hours at 23±2° C. with periodic mixing, and then homogenized by thoroughmixing with 4.75 g of the medium chain triglyceride Miglyol 812. Themixture can be allowed to age for at least 12 hours with periodicmixing. The resulting paste can be physically stable upon centrifugationat 3000 G and it can be centrifuged to remove trapped air. The paste isexpected to be soft, compliant, and easy to mechanically deform and toretain at 23±2° C. its shape after deformation. The paste is notexpected to be pourable at 23±2° C., but at 37±2° C. it could beextruded. At a continuous extrusion rate of 0.2 mL/hour, optionally from1.2 mL paste containing reservoirs replaced every 6 hours, 4.8 mL of thepaste containing 5.6 g or about 0.067 moles of magnesium carbonate wouldbe extruded over 24 hours into the mouth. With a pair of bilateraldevices 11.2 g or about 0.132 moles of magnesium carbonate would beextruded daily into the mouth.

Example 38. A 1.4 g/mL Magnesium Oxide Comprising Orally ExtrudablePaste e.g. for Managing a Neurological Disorder Like Alzheimer's Diseaseor Parkinson's Disease

Ingredients: Magnesium oxide, about 20 μm nominal particle size;Poloxamer 188; Miglyol 812 (Peter Cremer, Cincinnati, Ohio); de-ionizedwater.

0.8 g Poloxamer 188 can be dissolved in 5 g water then homogenized with24 g of magnesium oxide. The mixture can be allowed to age for 10 hoursat 23±2° C. with periodic mixing, and then homogenized by thoroughmixing with 4.75 g of the medium chain triglyceride Miglyol 812. Themixture can be allowed to age for at least 12 hours with periodicmixing. The resulting paste can be physically stable upon centrifugationat 3000 G and it can be centrifuged to remove trapped air. The paste isexpected to be soft, compliant, and easy to mechanically deform and toretain at 23±2° C. its shape after deformation. The paste is notexpected to be pourable at 23±2° C., but at 37±2° C. it could beextruded. At a continuous extrusion rate of 0.075 mL/hour, 1.8 mL of thepaste containing 2.5 g or about 0.064 moles of magnesium oxide would beextruded over 24 hours into the mouth. With a pair of bilateral devices5 g or about 0.13 moles of magnesium oxide would be extruded daily intothe mouth.

Example 39. An 800 mg/mL Trimebutine-Comprising Orally Extrudable Pastefor Irritable Bowel Syndrome Management

Ingredients: Trimebutine, about 20 μm nominal particle size; Poloxamer188; Miglyol 812 (Peter Cremer, Cincinnati, Ohio); de-ionized water.

0.8 g Poloxamer 188 can be dissolved in 1.5 g water then homogenizedwith 10 g of trimebutine. The mixture can be allowed to age for 10 hoursat 23±2° C. with periodic mixing, and then homogenized by thoroughmixing with 4.75 g of the medium chain triglyceride Miglyol 812. Themixture can be allowed to age for at least 12 hours with periodicmixing. The resulting paste can be physically stable upon centrifugationat 3000 G and it can be centrifuged to remove trapped air. The paste isexpected to be soft, compliant, and easy to mechanically deform and toretain at 23±2° C. its shape after deformation. The paste is notexpected to be pourable at 23±2° C., but at 37±2° C. it could beextruded. At a continuous extrusion rate of 0.03 mL/hour, 0.72 mL of thepaste containing 576 mg of trimebutine would be extruded over 24 hoursinto the mouth.

Example 40. An 800 mg/mL Curcumin-Comprising Orally Extrudable Paste forCancer Therapy

Ingredients: Curcumin, about 20 μm nominal particle size; Poloxamer 188;Miglyol 812 (Peter Cremer, Cincinnati, Ohio); de-ionized water.

0.8 g Poloxamer 188 can be dissolved in 1.5 g water then homogenizedwith 10 g of curcumin. The mixture can be allowed to age for 10 hours at23±2° C. with periodic mixing, and then homogenized by thorough mixingwith 4.75 g of the medium chain triglyceride Miglyol 812. The mixturecan be allowed to age for at least 12 hours with periodic mixing. Theresulting paste can be physically stable upon centrifugation at 3000 Gand it can be centrifuged to remove trapped air. The paste is expectedto be soft, compliant, and easy to mechanically deform and to retain at23±2° C. its shape after deformation. The paste is not expected to bepourable at 23±2° C., but at 37±2° C. it could be extruded. At acontinuous extrusion rate of 0.1 mL/hour, 2.4 mL of the paste containing1.92 g of curcumin would be extruded over 24 hours into the mouth.

Example 41. An 800 mg/mL Curcumin-Analog EF31-Comprising OrallyExtrudable Paste for Cancer Therapy

Ingredients: Curcumin-analog EF31, about 20 μm nominal particle size;Poloxamer 188; Miglyol 812 (Peter Cremer, Cincinnati, Ohio); de-ionizedwater.

0.8 g Poloxamer 188 can be dissolved in 1.5 g water then homogenizedwith 10 g of Curcumin-analog EF31. The mixture can be allowed to age for10 hours at 23±2° C. with periodic mixing, and then homogenized bythorough mixing with 4.75 g of the medium chain triglyceride Miglyol812. The mixture can be allowed to age for at least 12 hours withperiodic mixing. The resulting paste can be physically stable uponcentrifugation at 3000 G and it can be centrifuged to remove trappedair. The paste is expected to be soft, compliant, and easy tomechanically deform and to retain at 23±2° C. its shape afterdeformation. The paste is not expected to be pourable at 23±2° C., butat 37±2° C. it could be extruded. At a continuous extrusion rate of 0.1mL/hour, 2.4 mL of the paste containing 1.92 g of curcumin-analog EF31would be extruded over 24 hours into the mouth.

Example 42. An 800 mg/mL Curcumin-Analog UBS109-Comprising OrallyExtrudable Paste for Cancer Therapy

Ingredients: Curcumin-analog UBS109, about 20 μm nominal particle size;Poloxamer 188; Miglyol 812 (Peter Cremer, Cincinnati, Ohio); de-ionizedwater.

0.8 g Poloxamer 188 can be dissolved in 1.5 g water then homogenizedwith 10 g of curcumin-analog UBS109. The mixture can be allowed to agefor 10 hours at 23±2° C. with periodic mixing, and then homogenized bythorough mixing with 4.75 g of the medium chain triglyceride Miglyol812. The mixture can be allowed to age for at least 12 hours withperiodic mixing. The resulting paste can be physically stable uponcentrifugation at 3000 G and it can be centrifuged to remove trappedair. The paste is expected to be soft, compliant, and easy tomechanically deform and to retain at 23±2° C. its shape afterdeformation. The paste is not expected to be pourable at 23±2° C., butat 37±2° C. it could be extruded. At a continuous extrusion rate of 0.1mL/hour, 2.4 mL of the paste containing 1.92 g of curcumin-analog UBS109would be extruded over 24 hours into the mouth.

Example 43. Showing the Shape and Dimensions of an Exemplary Model ofthe Oral Drug Pump

Testing for comfort of various pump models in volunteers that cancomprise about 0.8 mL of the LD/CD paste pharmaceutical compositionshowed that for comfort of wear the surfaces must not have corners oredges that are sharp, i.e., that the edges and corners should be aboutrounded; furthermore the surfaces, particularly those contacting buccalsurfaces should be smooth. Pump models of obround shape and 0.81 mLLD/CD paste pharmaceutical composition volume were particularlycomfortable to wear and did not substantially alter the appearance ofthe face. The width of the pumps (their dimension from the vestibularsurface of the teeth outward) was most important for comfort, followedby their length. When pumps span a third tooth (i.e. more than twoteeth) and the teeth were even slightly misaligned there were visiblechanges in the appearance of the face of the wearer. Tests in fourpeople showed that tooth attached obround pumps that were 0.27″ wide,0.50″ high, and 0.95″ long were particularly comfortable, did notinterfere with speech, did not interfere with swallowing food or drink,and did not substantially alter the appearance of the face of thewearer.

Example 44. Describing the Welding of a Silver Diaphragm to a TitaniumHousing to Form Hermetically Sealed Chambers with Ports

Hermetically sealed obround-shaped test units were made. The obroundhermetically sealed units were 0.27″ wide, 0.50″ high, and 0.95″ long.Their housing was Grade 2 titanium and their 0.50″×0.95″, 0.03 mm thickdiaphragms were commercially pure, fully annealed silver foils. As shownin FIG. 27, hermetically sealed chambers can be formed by resistancewelding of Ti—Ag—Ti (in ambient air and without using a flux) where therim (i.e. the flange) of the silver foil diaphragm was welded.Resistance brazing coupons 106 were welded to silver diaphragm 90. Forthe resistance welding a sequence of unequal duration pulses of unequalcurrents were passed through the Ti—Ag—Ti structure while its parts werepressed together. Only the shortest and largest current pulse meltedpart or most of the silver diaphragm rim; it did not melt most of thesilver diaphragm nor did it melt the titanium housing.

Example 45. Describing the Shape, Method of Forming and Material of anExemplary Diaphragm

To assess the formability of the diaphragm, pure silver sheet of 0.025and 0.03 mm thickness were procured and a stamp die block, cover plate,and punch were designed to form diaphragms per the schematic drawing ofFIG. 28.

Diaphragms were also made using the tool shown in FIG. 29. Thediaphragms were slightly oversized to allow for spring-back. They werealso made of a sheet of 0.03 mm thick commercially pure, fully annealed,silver foil. The silver foil sheet was cut to the approximate size ofthe surface of the tool, placed on the surface of the tool and forcedinto the cavity by pressing on the flat surface of the tool. By pressingon the tool while the worked piece was rotated the silver foil was madeto conform to the bottom of the tool. After stamping, some diaphragmswere wrinkled at their rims (i.e. at their flanges) as seen in thephotograph of FIG. 30. To straighten the wrinkles (i.e. to reduce theirheights) the rims were flattened by coining. The diaphragms were thentested for absence of light passing through pinholes or tears, thentrimmed with a blade along the grooves of the tool shown in FIG. 29.

Example 46. Showing the Welding of Titanium Housing Parts and TitaniumFoil to Form Hermetically Sealed Chambers

Test housings were machined from Grade 2 titanium and diaphragms weremade of a 0.05 mm thick commercially pure, fully annealed silver foilsheet. The test housings contained fittings that allowed testing forhermeticity, as shown in FIG. 31.

A benchtop medium-frequency inverter Amada Miyachi resistance welder wasused. A pre-weld current pulse was passed prior to application of thewelding current pulse. The pre-weld current pulse was of a duration 40times longer and a current that was 45% of the welding current pulse.After application of the brief welding current pulse, the now joinedparts were annealed in an oven for 30 min at 600° C. then allowed tocool to room temperature over 45 minutes or more. To test chambers forthe hermeticity of their welds, each chamber was connected through itsport to a helium leak tester known as “sniffer” according to the USMilitary's standard MIL-STD-750E hermetic seal test, i.e., leak test.Each of five units passed tests showing hermeticity of the seals and thediaphragms for the specification “time to exchange 50% atmosphereof >>17.6 years”, i.e., there were no detectable leaks through eitherthe diaphragms or through the titanium/silver joints (i.e., welds).

Example 47. Showing Incomplete Delivery and Variation in Extrusion Rateby a Pump without a Grooved Drug Chamber Wall

A re-usable testing tool referred to as “test bed” was machined, asshown in FIG. 32. It simulated the pump and measured the flow rate ofdifferent LD/CD pharmaceutical composition formulations, at differentgas pressures, with flow-controlling nozzles of different internaldiameter and length. The test bed comprised two blocks machined to thedimensions of the obround pump geometry, separated by a diaphragm, theblocks and the diaphragm pressed together to prevent leakage of theLD/CD paste pharmaceutical composition and of the gas. The blocks of thetest bed comprised two identical cavities in the housings of thepropellant chamber 103 and the drug chamber 104, one cavity 103 having aport for pressurizing with a gas (typically CO₂) to simulate thepressure from a propellant, and the other 104 containing a port 105 andnozzle 98 for the outlet of the drug formulation.

The two cavities sandwiched a 0.030 mm thick pinhole-free silverdiaphragm. The silver diaphragm was prepared by manually pressing asheet of 0.030 mm silver into a mold that simulates the drug cavity sideof the pump. The diaphragm was placed into drug the cavity, the drug wasthen injected beneath it until the cavity was filled, then the flowcontrolling nozzle was attached.

The weight of the extruded LD/CD paste pharmaceutical composition wasmonitored with an analytical balance. The figure below shows the typicaltime dependence of the extruded mass. In the particular experimentdescribed the pressure of the propelling CO₂ was kept constant at 80 psiand a 20 mm long 0.51 mm internal diameter polyethylene terephthalatenozzle was attached. FIG. 33 is a graph of the amount of thepharmaceutical composition delivered versus time and shows that theslope was not constant over the 100 min extrusion, i.e., that the rateof extrusion was not constant. The non-constant flow rate in the sameexperiment is shown also in the FIG. 34, where the time dependence ofthe flow rate is plotted.

The drug was not only delivered non-linearly, but was also notcompletely delivered from the drug reservoir. FIG. 35 shows the drugremaining in the drug chamber after the drug had ceased to flow from thepump.

Example 48. Showing Lesser Variability in Flow Rate and Delivery of aLarger Fraction of the Drug when the Drug Chamber Wall is Grooved

The experiment of Example 47 was repeated but with flow channel-forminggrooves in the housing wall of the LD/CD drug-containing chamber. Thechannels were designed to provide a path for the drug to flow when thediaphragm collapses into the drug-containing chamber. As the drugempties the diaphragm typically makes contact with the bottom of thehousing, thereby preventing or slowing the flow of the drug-comprisingfluid from part of the chamber, i.e., trapping the drug-comprising fluidbetween the collapsed diaphragm and the chamber's wall. The photographof FIG. 36 shows the grooves 99 in the housing wall of thedrug-containing chamber 104 of the test bed. As seen in FIG. 37 thegrooves improved the constancy of the flow rate of a LD/CD comprisingpaste, but did not make it actually constant. As seen in FIG. 38, wherethe time dependence of the flow rate is plotted, the flow rate continuedto decline throughout the 160 min run.

Example 49. Showing the about Constant Rate Delivery of a DrugComprising Composition and Near Complete Delivery of the Drug in theChamber when the Flow Channels are Flow-Controlling Tubes in the Chamber

The testing tool (test bed) was similar to that of Examples 47, but nowcomprised two tubular flow channels 98 as shown in FIG. 39. The tubesalso served as flow-rate controlling nozzles. Their internal diameterwas about 0.36 mm and their length was about 40 mm. The tubes werepositioned in grooves 97 cut in the housings of the propellant chamber103 and the drug chamber 104 and extended outside of the housing. Theflow rate, controlled by the tubes or nozzles, now maintained a constantflow rate of approximately 2.2 mg/min. FIG. 40 shows a typical mass vs.time run over a period of 5.5 hrs. The time dependence of the flow rateshown in FIG. 41 confirmed that the flow rate was now constant withinbetter than ±7.5%.

Example 50. Showing that the Rate of Galvanic Corrosion inTitanium-Silver Joints is Slow

In the absence of air or oxygen metals can corrode by reacting withwater. The corrosion requires an oxidation reaction whereby the metal isoxidized to its oxide or its hydroxide and a reduction reaction wherebywater is reduced to molecular hydrogen or to a metal hydride. Becausethe currents associated with the two rates are equal, the corrosion rateof a particular metal can be slow either if the oxidation or thehydrogen evolution is slow. If two different metals are contacted, theless noble metal is oxidized while the more noble metal is reduced toits hydride or evolves H₂. The rate of oxidation of the less noble metalcan depend on its passivating oxide or hydroxide layer that can slow orprevent mass transport between the solution and the metal. The corrosionrate depends on the pH of the composition, typically 4±1 for theextruded the LD/CD paste pharmaceutical compositions. To assess therates of corrosion, the currents flowing between shorted electrode pairsof about 2 cm² solution-contacting area in a 0.1 M citrate buffer pH 4solution (made with trisodium citrate and citric acid) were measuredunder air and under nitrogen at about 23±3° C. after about 24 hour aging(while shorted) in the buffer solution, both without adding carbidopaand with enough carbidopa added to saturate the solution. The resultsare summarized in the Table 20.

TABLE 20 Corrosion Currents. Corrosion Carbidopa Current, Anode CathodeAir or N₂ added μA Titanium Tin N₂ no 60 Titanium Tin N₂ no 40 TitaniumSilver Air no 0.15 Titanium Silver N₂ no 0.1 Titanium Silver N₂ yes 0.2316 stainless steel Tin N₂ yes 30 316 stainless steel Tin N₂ yes 30 316stainless steel Silver N₂ no 0.5 316 stainless steel Silver N₂ no 1 316stainless steel Silver Air Yes 1.5

The surface of the tin was visibly roughened, possibly because ofreduction to tin hydride. The surfaces of the titanium, the silver, andthe 316 stainless steel appeared unchanged to the eye. The data showmuch more rapid corrosion of the couples with tin than with silver. Thedata show possibly acceptable corrosion for the 316 stainlesssteel-silver couple. The least corroding couple is, however, thetitanium/silver couple, indicating the absence of substantial corrosionof joints formed of the two metals, for example of titanium welded withsilver.

Example 51. Showing that a pH 2.7-pH 3.3 Suspension Comprising anAntimicrobial Excipient, a Transition Metal Complexing Agent, 625 mg/mL(3.17 M) LD, 156 mg/mL (0.74 M) CD, and Poloxamer 188 Surfactant isPhysically Stable when Centrifuged for 1 Hour at about 16,000 G

Most of the LD and most of the CD in the suspension is particulate,i.e., the solid drugs are not dissolved. The suspension comprises 50.0weight % (w/w) LD; 12.5 weight % CD; 24.1 weight % Miglyol 812; 5.0weight % of Poloxamer 188; 7.9 weight % water; 0.3 weight % benzoicacid; 0.05 weight % EDTA (free acid form); 0.05 weight % EDTA disodiumsalt; and 0.1 weight % BHA. It is prepared as follows: (a) the LD (5 g)and CD (1.25 g) powders are mixed for 15 min to homogeneity; (b) thePoloxamer 188 (0.5 g) is mixed with deionized water (0.79 g) in which 5mg of EDTA (free acid) and 5 mg disodium EDTA are dissolved. The mixtureis warmed to about 60° C. and homogenized by thorough mixing; (c) the LDand CD powder mixture of (a) and 10 mg of BHA is added to the Poloxamer188 and water of (b) and mixed thoroughly. The mixture is kept atambient temperature for 24 hours; (d) after the 24 hours, 2.41 g ofMiglyol 812 containing 30 mg of benzoic acid and 10 mg of BHA are added,mixed thoroughly, then the mixture is aged at ambient temperature for atleast 6 hours, remixed, then centrifuged. There is no visiblesedimentation of the solid drug particles nor is there any visible phaseseparation of the oil and the water upon 1 hour centrifugation at 13,000rpm providing an acceleration of about 16,000 G (G being the gravity atabout sea level), suggestive of shelf life physical stability for about22 months at 1 G and room temperature. The pH of the mixture as measuredwith a pH glass electrode at about 23±3° C. is between about 2.7 andabout 3.3. The suspension remains unchanged, i.e., homogeneous, afterstorage for 24 hours at about 25° C., 40° C., and 60° C.

Example 52. Showing that a Thiol-Containing Suspension Containing 625mg/mL (3.17 M) LD, 156 mg/mL (0.74 M) CD, and Poloxamer 188 SurfactantMay be Physically Stable when Centrifuged for 1 Hour at about 16,000 Gand May Generate Little or No Hydrazine when Stored Under Nitrogen atabout 30° C.

Most of the LD and most of the CD in the suspension is particulate,i.e., the solid drugs are not dissolved. The suspension comprises 49.9weight % (w/w) LD; 12.4 weight % CD; 0.2 weight % cysteine; 24.4 weight% Miglyol 812; 5.0 weight % of Poloxamer 188; 7.9 weight % water inwhich 0.05 weight % of EDTA (free acid) and 0.05 weight % disodium EDTAare dissolved; and 0.1 weight % BHA. It is prepared as follows: (a) theLD (4.99 g) and CD (1.24 g) and cysteine (0.2 g) powders are mixed for15 min to homogeneity; (b) the Poloxamer 188 (0.5 g) is mixed withdeionized water (0.79 g) in which 5 mg of EDTA (free acid) and 5 mgdisodium EDTA are dissolved. The mixture is warmed to about 60° C. andhomogenized by thorough mixing; (c) the LD and CD powder mixture of (a)and 10 mg of BHA are added to the Poloxamer 188 and water of (b) andmixed thoroughly. The mixture is kept at ambient temperature for 24hours; (d) after the 24 hours, 2.44 g of Miglyol 812 containing 30 mg ofbenzoic acid and 10 mg of BHA are added, mixed thoroughly, then themixture is aged at ambient temperature for at least 6 hours, remixedthen centrifuged. There is no visible sedimentation of the solid drugparticles nor is there any visible phase separation of the oil and thewater upon 1 hour centrifugation at 13,000 rpm, providing anacceleration of about 16,000 G (G being the gravity at about sea level),suggestive of shelf life physical stability for about 22 months at 1 Gand room temperature. The suspension remains unchanged, i.e.,homogeneous, after storage for 24 hours at about 25° C., 30° C., 40° C.,and 60° C. The concentration of hydrazine increases by less than 0.5μg/mg when the mixture is stored under nitrogen for 1 month at about 30°C.

Example 53. Clinical Trial of Frequent Intermittent Delivery of a LD/CDSuspension to Patients with Advanced Parkinson's Disease

The clinical trial was an open-label, single-center study of 18Parkinson's disease patients who experienced ≧2 hours of OFF time perday while on their regular anti-PD medications. Standard intermittentoral LC/CD Sinemet tablets were compared with the same total doses ofLD/CD suspension delivered into the mouth every 5-10 minutes using anoral syringe. The LD/CD suspensions were prepared by dispersing theSinemet tablets in a small amount of water. Patients were admitted tothe clinic on Day 1 for baseline evaluations. On Day 2 (the “ControlDay”), LD/CD was administered as commercially available LD/CD tablets ateach patient's pre-baseline dosing regimen. Plasma levels of levodopa aswell as ON and OFF time were measured repeatedly over the course of 8hours. On Day 3 (the “PK Day”), a suspension of LD/CD was administeredintraorally every 5-10 minutes over a period of 8 hours at a dose equalto the total dose of standard oral LD/CD that the patient consumed overthe same 8-hour period on the Control Day, and plasma levels of levodopawere obtained. On Day 4 (the “Efficacy Day”), each patient received hisor her first LD/CD morning dose as an oral tablet at the same dosage asthe first morning dose on the Control Day. They then received thebalance of the total 8-hour dose that they took on the Control Day byway of intraoral administration of a suspension of LD/CD every 5-10minutes over a period of 8 hours. ON and OFF time were assessed as onDay 2. Patients were then discharged from the clinic on their standardmedication and returned on Day 18 for a safety evaluation.

The primary endpoint was defined as the variability of the levodopaconcentrations; standard intermittent oral and semi-continuous intraoraladministration were compared. Pharmacokinetic endpoints includeddeviation from linearity and the mean levodopa fluctuation index((C_(max)−C_(min))/C_(average)). Efficacy was measured byneurologist-based assessment of motor state and dyskinesia at 30-minuteintervals over the 8 hours and by UPDRS Part III, assessed at 0, 2, 4,and 8 hours on the Control Day (Day 2) and the Efficacy Day (Day 4).

Safety parameters measured included physical examinations, neurologicalexaminations, ECGs, vital signs, blood and urine laboratory assessments,and oral site assessments by both the neurologist and the patient.

Patient baseline characteristics are shown in Table 21.

TABLE 21 Patient Demographic and Baseline Characteristics. Mean (SD) orN (%) Range Age (years) 68.0 (8.9) 44-81 Gender (male) 11 (61.1%) Race(white) 18 (100%) Weight (kg) 73.4 (14.8) 45-98 Height (cm) 170.9 (11.4)144-190 BMI (kg/m²) 24.1 (3.8) 19-32 Total daily dose of LD (mg) 781(228)  350-1075 Dosing frequency (number of doses per day) Time since PDdiagnosis (years) 13.8 (6.5)  6-35

Concomittant anti-PD medications taken by the study participants areshown in Table 22.

TABLE 22 Other Anti-PD Medication. N % At least one anti-PD medicationother than LD 17 94.4 Amantadine 6 33.3 Dopamine agonists 6 33.3Pramipexole 1 5.6 Ropinirole 4 22.2 Rotigotine 1 5.6 MAO-B inhibitors 1477.8 Rasagiline 13 72.8 Selegiline 1 5.6 COMT inhibitors 9 50 Entacapone7 38.9 Tolcapone 2 11.1

For the primary endpoint, statistically significant improvements wereobserved for variability in plasma levodopa concentration (as determinedby linearity) and for reduction in 1-hour and 2-hour fluctuation indexes(p<0.001 for each). FIG. 42 shows the reduction in the fluctuation indexfor each 2-hour window during the study.

As shown in Table 23, OFF time was reduced by 43% (p<0.001). The UPDRSPart III motor score improved (p=0.010), confirming reduce motorimpairment in the patients. As shown in FIG. 43, OFF time was reduced in15 out of 18 patients, was unchanged in 3 patients, and increased in 0patients.

TABLE 23 Motor State. Intermittent Tablets (Day 2) Continuous Delivery(Day 4) State Mean (SEM) Mean (SEM) OFF 2.20 (0.30) 1.26 (0.22)Troublesome dyskinesia 0.00 (0.00) 0.39 (0.33) ON without troublesome5.79 (0.45) 6.35 (0.47) dyskinesia SEM = Standard error of measurement

No clinical study related adverse events were observed. In particular,local tolerability appeared good: no gum or mucosal irritation, redness,or ulceration was observed by physician inspection in any patient at anyobservation. Furthermore, no patient reported any complaint abouthis/her mouth at any time.

Example 54. Chemical Instability of Dilute, Commercially Available,Duodopa LD/CD Gel for Intestinal Infusion

In animal studies, hydrazine shows notable systemic toxicity,particularly upon inhalation. Hydrazine is also hepatotoxic, has CNStoxicities (although not described after oral treatment), and isgenotoxic as well as carcinogenic. Consequently, it is important tominimize hydrazine formation during storage of CD or LD/CD formulations.

Duodopa™ (sold as Duopa in the United States), a LD/CD suspension forcontinuous intraduodenal infusion, degrades during storage and produceshydrazine. The average recommended daily dose of Duodopa is 100 mL,containing 2 g levodopa and 0.5 g CD. The maximum recommended daily doseis 200 mL. According to the labeling, this includes hydrazine at up toan average exposure of 4 mg/day, with a maximum of 8 mg/day. In order tomeet these exposure limits, Duodopa's labeling in the United Statesrequires frozen storage and its labeled shelf life is 12 weeksrefrigerated (after thawing). The concentrations of LD and CD in Duodopaare 20 mg/mL and 5 mg/mL, respectively.

Six sealed 100 mL packages of commercial Duodopa were purchased andstored according to the storage instructions in the labeling. Hydrazineconcentrations of three packages were measured by HPLC immediately uponthawing (t=0) and provided concentrations of 547, 676, and 662 μg ofhydrazine per gram of LD+CD (average=629 μg hydrazine/g LD+CD). Thehydrazine concentrations of the three remaining packages were measuredafter 12 weeks refrigerated storage at 2-8° C. and providedconcentrations of 3,653, 3,725, and 3,729 μg of hydrazine per gram ofLD+CD (average=3,702 μg hydrazine/g LD+CD).

Example 55. Superior Stability of Concentrated LD/CD Suspensions inEmulsions of the Invention

Three LD/CD suspensions of the invention (labeled F16C, F41C, and F46C)were prepared according to the compositions of Table 24, packaged intoglass vials, and placed on stability at five storage temperatures: −20,2-8, 25, 30, and 40° C. Vials were prepared with the formulations storedunder air as well as nitrogen blanketed. The samples were evaluated forphysical and chemical stability at t=0, 1, 2, 3, and 6 months.

TABLE 24 Compositions of F16C, F41C, and F46C for stability study (%)F16C F41C F46C LD (micronized) 50 50 50 CD (micronized) 12.5 12.5 12.5Polysorbate 60 5 — — Poloxamer 188 — 5 — Cremophor RH40 — — 5 Miglyol812 24.4 24.4 23.9 BHA 0.1 0.1 0.1 DI-H₂O 8.0 8.0 8.0 Sucralose(Spectrum, NF grade) — — 0.5

Physical stability was assessed by one hour centrifugation at about16,000 G (G being the gravity at about sea level), which would besuggestive of shelf life physical stability for about 22 months at 1 G.Samples passed the test if there was no visible sedimentation of thesolid drug particles nor was there any visible phase separation of theoil and the water. Results of the centrifugation test are shown in Table25. F16C and F46C were physically stable when stored refrigerated for 6months. F41C was physically stable when stored at 2-8, 25, 30, and 40°C. for 6 months.

TABLE 25 Physical stability during 6 month real time stability studyCentrifugation test comparison (1M, 2M, 3M & 6M) Centrifugation TestF16C F41C F46C Storage 6M 6M 6M temp. @ @ @ (° C.) T₀ 1M 2M 3M 6M N₂ T₀1M 2M 3M 6M N₂ T₀ 1M 2M 3M 6M N₂ −20 P F F F F F P F F F F F P P P P F F2 to 8 P P P P P P P P P P P P P P P 25 F F F F F P P P P P P P F F F 30F F F F F P P P P P F F F F F 40 F F F F F P P P P P F F F F F M =months, F = fail, P = pass

Chemical stability was assessed by the amount of hydrazine in thesamples as measured by HPLC. Table 26 provides the measured hydrazineamounts, expressed as μg hydrazine per gram of LD+CD. Hydrazine at 6months for F16C, F41C, and F46C were 89, 391, and 142 μg hydrazine pergram of LD+CD, respectively, for the samples stored in vials withnitrogen blanketing. In contrast to the average of 3,702 μg hydrazineper gram of LD+CD found in Duodopa after storage for 12 weeks, only 7and 9 μg hydrazine per gram of LD+CD were found in the F41C and F46C,respectively, after storage for 3 months at 2-8° C. with nitrogenblanketing.

Comparing these results to those of Example 53, after storage underidentical conditions the inventive formulations contain a factor of 400×less hydrazine than the commercially available Duodopa product.

TABLE 26 Chemical stability during 6 month real time stability studyHydrazine level comparison (1M, 2M, 3M, and 6M) Hydrazine (μg per g ofLD + CD) Storage F16C F41C F46C temp. 6M Under N₂ Under N₂ (° C.) T₀ 1M2M 6M @N₂ T₀ 1M 2M 3M 6M 3M 6M T₀ 1M 2M 3M 6M 3M 6M −20 4.5 5.6 5.3 8.98.3 3.4 1.9 3.5 5.5 11.3 N/D 10.4 3.9 2.5 4.7  7.4 5.2 6.8 6.5 2 to 86.0 6.8 18.1 19.5 2.6 6.6 9.9 37.9 6.8 48.6 3.5 9.6  9.6 11.4 9 11.1 259.9 27.5 34.4 30.5 13.5 12.7 30.2 92.7 30.4 57.4 19.1 51.9  25.1* 56.3N/D 16 30 75.8 185.8 182.6 68.1 55.4 176.5 166.6 785.1 46.3 395.7 48.2139.4 150.2 48.2 N/D 36.4 40 156.2 205.1 205.9 89.4 122.8 180.1 161.4791.2 64.4 390.6 113.8 171.4 176.9 146.2 N/D 142.2 M = months

Table 27 provides the apparent pH of the formulations during thestability studies at t=0, 1, 2, and 3 months. As can be seen from thedata, the pH is less than pH 5 and remains less than pH 5 after 3 monthsstorage at 25° C.

TABLE 27 pH during 3 month real time stability study pH at differentstorage conditions for 1 M, 2 M and 3 M pH @ pH @ pH @ pH @ pH @ SampleID −20° C. −2-8° C. 25° C. 30° C. 40° C. F16C_1M 3.8 3.7 3.4 4.4 4.2F16C_2M 3.8 3.8 3.7 4.8 4.6 F16C_3M 4.1 4.5 4.8 4.5 4.9 F16C_3M_N₂ 3.94.0 4.5 4.3 4.7 F41C_1M 3.5 3.5 3.8 4.5 4.5 F41C_2M 4.1 4.5 4.8 4.5 4.9F41C_3M 4.0 4.4 4.0 4.4 5.1 F41C_3M_N₂ 4.1 4.1 4.0 4.3 4.8 F46C_1M 4.04.0 4.1 4.3 4.3 F46C_2M 5.3 4.7 4.9 4.7 4.8 F46C_3M 4.8 4.7 4.1 4.7 4.7F46C_3M_N₂ 4.8 4.4 4.2 4.6 4.9

In this experiment it was discovered that the stabilities of similarlymade drug-comprising pastes for continuous extrusion into the mouthdepend on their surfactants.

OTHER EMBODIMENTS

Various modifications and variations of the described invention will beapparent to those skilled in the art without departing from the scopeand spirit of the invention. Although the invention has been describedin connection with specific embodiments, it should be understood thatthe invention as claimed should not be unduly limited to such specificembodiments. Indeed, various modifications of the described modes forcarrying out the invention that are obvious to those skilled in the artare intended to be within the scope of the invention.

Other embodiments are in the claims.

What is claimed is:
 1. A pharmaceutical composition comprising asuspension comprising (i) an oil, and (ii) from about 35% to 70% (w/w)solid drug particles comprising levodopa and/or carbidopa, wherein thepharmaceutical composition is physically stable and wherein saidpharmaceutical composition is a non-pourable, plastically deformablepaste.
 2. The pharmaceutical composition of claim 1, wherein aftercentrifugation for 1 hour at an acceleration of about 5,000 G at 25±3°C. the concentrations of drug in the layer containing the top 20 volume% and the layer containing the bottom 20 volume % of the compositiondiffer by less than 4%.
 3. The pharmaceutical composition of claim 2,wherein said suspension has a dynamic viscosity of at least 10,000 cP at37° C.
 4. The pharmaceutical composition of claim 1, wherein saidsuspension comprises less than or equal to about 30% (w/w) of said oil.5. The pharmaceutical composition of claim 4, wherein said suspensioncomprises greater than or equal to about 19% (w/w) of said oil.
 6. Thepharmaceutical composition of claim 3, wherein said suspension compriseswater and a surfactant.
 7. The pharmaceutical composition of claim 1,wherein said solid drug particles comprise carbidopa, and wherein saidpharmaceutical composition comprises less than 4 μg of hydrazine per mgof carbidopa after 12 month storage at 5±3° C., or less than 1 μg ofhydrazine per mg of carbidopa after 3 month storage at 5±3° C.
 8. Thepharmaceutical composition of claim 1, said pharmaceutical compositioncomprising a suspension comprising (i) from about 35% to 70% (w/w) soliddrug particles comprising levodopa and/or carbidopa, (ii) from 19% to30% (w/w) of one or more water-immiscible compounds comprising an oil,(iii) from 2% to 16% (w/w) water, and (iv) from 1% to 8% (w/w)surfactant, wherein the pharmaceutical composition is suitable forcontinuous or frequent intermittent intra-oral delivery.
 9. Thepharmaceutical composition of claim 8, wherein said suspension has adynamic viscosity of at least 10,000 cP at 37° C.
 10. The pharmaceuticalcomposition of claim 9, wherein said suspension has a dynamic viscosityof at least 100,000 cP at 37° C.
 11. The pharmaceutical composition ofclaim 9, wherein after centrifugation for 1 hour at an acceleration ofabout 5,000 G at 25±3° C. the concentrations of drug in the layercontaining the top 20 volume % and the layer containing the bottom 20volume % of the composition differ by less than 4%.
 12. Thepharmaceutical composition of claim 9, wherein the shelf life of saidpharmaceutical composition is 6 months or longer at 5±3° C. and saidpharmaceutical composition does not substantially cream or sediment whenstored for 6 months at 5±3° C.
 13. The pharmaceutical composition ofclaim 9, wherein said suspension is a non-pourable, plasticallydeformable paste, and retains its shape at ambient temperature followingextrusion through an orifice.
 14. The pharmaceutical composition ofclaim 9, wherein said pharmaceutical composition comprises an emulsion.15. The pharmaceutical composition of claim 9, wherein the suspensioncomprises greater than 50% (w/w) solid drug particles.
 16. Thepharmaceutical composition of claim 9, wherein the D₅₀ of the solid drugparticles is less than or equal to 25 μm when measured by lightscattering with the particles dispersed in a non-solvent.
 17. Thepharmaceutical composition of claim 16, wherein the D₅₀ of the soliddrug particles is greater than or equal to 1 μm when measured by lightscattering with the particles dispersed in a non-solvent.
 18. Thepharmaceutical composition of claim 9, wherein said suspension comprisesless than or equal to about 12% (w/w) water.
 19. The pharmaceuticalcomposition of claim 18, wherein said suspension comprises 8±2% (w/w)water.
 20. The pharmaceutical composition of claim 9, wherein said oilcomprises a saturated fatty acid triglyceride, an unsaturated fatty acidtriglyceride, a mixed saturated and unsaturated fatty acid triglyceride,a medium-chain fatty acid triglyceride, canola oil, coconut oil, palmoil, olive oil, soybean oil, sesame oil, corn oil, or mineral oil. 21.The pharmaceutical composition of claim 20, wherein said oil comprises amedium-chain fatty acid triglyceride.
 22. The pharmaceutical compositionof claim 9, wherein said pharmaceutical composition comprises anon-ionic surfactant.
 23. The pharmaceutical composition of claim 22,wherein said non-ionic surfactant comprises a polyglycolized glyceride,an alkyl saccharide, an ester saccharide, or a polysorbate surfactant.24. The pharmaceutical composition of claim 22, wherein said non-ionicsurfactant comprises a poloxamer.
 25. The pharmaceutical composition ofclaim 22, wherein said suspension comprises about 5±2% (w/w) of saidsurfactant.
 26. The pharmaceutical composition of claim 9, wherein thepH of the composition measured by inserting a glass walled pH electrodeinto the formulation is less than pH 5 and remains less than pH 5 after3 months storage at 25° C.
 27. A pharmaceutical composition comprising asuspension comprising (i) from about 35% to 70% (w/w) solid drugparticles comprising levodopa and/or carbidopa, (ii) from 19% to 30%(w/w) of one or more water-immiscible compounds comprising an oil, (iii)from 2% to 16% (w/w) water, (iv) from 1% to 8% (w/w) surfactant, and (v)benzoic acid or a benzoate salt wherein the pharmaceutical compositionis physically stable, wherein the pharmaceutical composition is suitablefor continuous or frequent intermittent intra-oral delivery, and whereinsaid suspension has a dynamic viscosity of at least 10,000 cP at 37° C.28. A pharmaceutical composition comprising a suspension comprising (i)from about 35% to 70% (w/w) solid drug particles comprising levodopaand/or carbidopa, (ii) from 19% to 30% (w/w) of one or morewater-immiscible compounds comprising an oil, (iii) from 2% to 16% (w/w)water, (iv) from 1% to 8% (w/w) surfactant, and (v) EDTA or its salt orsalts, wherein the combined concentrations of EDTA and its salt or saltsis between 0.05 weight % and 0.25 weight %, wherein the pharmaceuticalcomposition is physically stable, wherein the pharmaceutical compositionis suitable for continuous or frequent intermittent intra-oral delivery,and wherein said suspension has a dynamic viscosity of at least 10,000cP at 37° C.
 29. The pharmaceutical composition of claim 1, wherein saidpharmaceutical composition comprises: (i) from about 50% to about 75%(w/w) of said solid drug particles; (ii) 8±2% (w/w) water, (iii) 24±2%(w/w) of said oil, wherein said oil is a medium-chain fatty acidtriglyceride; and (iv) 5±2% (w/w) of a surfactant that is a poloxamer.